Acute Lymphoblastic Leukemia (ALL) Treatment Regimens

Acute Lymphoblastic Leukemia (ALL) Treatment Regimens

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.


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These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The National Comprehensive Cancer Network Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶CNS Prophylaxis1,a

PROTOCOL1,b

REGIMEN and DOSING

Intrathecal (IT) Cytarabine2-4

Day 1: Cytarabine 50-100mg intrathecal with or without 50mg Hydrocortisone (preservative free).

Note: Frequency and duration are dependent on CNS disease status and risk of CNS relapse.

IT Cytarabine/ Methotrexate/ Hydrocortisone2-4

Day 1: Cytarabine 50-100mg intrathecal, with:

Day 1: Methotrexate 12-15mg intrathecal, with:

Day 1: Hydrocortisone 50-100mg (preservative-free) intrathecal.

Note: Frequency and duration are dependent on CNS disease status and risk of CNS relapse.

IT Methotrexate2-4

Day 1: Methotrexate 12-15mg intrathecal with or without 50mg Hydrocortisone (preservative-free).

Note: Frequency and duration are dependent on CNS disease status and risk of CNS relapse.

▶Newly-diagnosed ALL1,a

PROTOCOL1,b

REGIMEN and DOSING

Adolescents and Young Adults (AYA) (15-39 years)c

Philadelphia Chromosome-Positive [Ph (+)] Diseased

Other Recommended Regimens

CALGB 107015,e

Course I (First Induction):

Days 1-7: Dasatinib 140 mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV.

Course II (If ≤20% lymphoblasts in marrow at Day 15):

Days 1-7: Dasatinib 140 mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV.

Course II (If >20% lymphoblasts in marrow at Day 15):

Days 1-7: Dasatinib 140 mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV.

Vincristine and Daunorubicin also administered.

Course III (Second Induction for patients not in complete remission (CR) or CR with incomplete hematologic recovery (CRi):

Patients received Dasatinib, Cyclophosphamide, Vincristine, Daunarubicin, Dexamethasone.

Course IV (CNS Prophylaxis):

Patients received Dasatinib, IV Vincristine, and IV, oral, and intrathecal Methotrexate.

Course V :

Patients treated with stem cell transplantation or chemotherapy.

Course VI (Maintenance):

Dasatinib

Starting on Day 30 of Course V and continued for 12 months and until 2 consecutive negative BCR-ABL1 RT-PCR assays 3 months apart or relapse.

Corticosteroids + TKI6,7,e

• Dasatinib + Prednisone

PrePhase:

Days (-7-[-1]): Prednisone 10-60mg/m2 in increasing doses.

Induction Therapy:

Dasatinib 70mg twice daily for 84 days

Prednisone 60mg/m2 daily (capped at 120mg daily) administered until Day 24 and then tapered and stopped at Day 32.

Days 22,43: Methotrexate intrathecal.

• Imatinib + Prednisone

PrePhase:

Days (-7-[-1]): Prednisone 10-40mg/m2 in increasing doses.

Induction Therapy:

Days 1-45: Imatinib 800mg orally

Days 1-45: Prednisone 40mg/m2

Note: Induction Therapy with Corticosteroid + Nilotinib is also a recommended regimen.

Note: These regimens are used for induction therapy and additional therapy is needed.

EsPhALL Regimen: TKI and a backbone of the Berlin- Frankfurt-Munster regimen8,9,e

• Imatinib-Based Therapy

Protocol IB:

Day 1,28: Cyclophosphamide 1000mg/m2 IV

Days 1-28: 6-Mercaptopurine 60mg/m2 orally

Days 3-6, 10-13, 17-20, 24-27: Cytarabine 75mg/m2 subcutaneous

Days 3,7: Methotrexate 12mg intrathecal

Days 1-28: Imatinib 300mg/m2 orally.

Consolidation Block HR1:

Days 1-5: Dexamethasone 20mg/m2 oral or IV

Days 1,6: Vincristine 1.5mg/m2 IV

Day 1: Methotrexate 5000mg/m2 IV

Day 5: Cytarabine 2000mg/m2 IV

Day 6: L-Asparaginase 25,000 IU/m2 IM

Day 2-4: Cyclophosphamide 200mg/m2 IV

Day 1: Methotrexate 12mg intrathecal

Day 1: Cytarabine 30mg intrathecal

Day 1: Prednisone 10mg intrathecal

Days 6-20: Imatinib 300mg/m2 orally.

Consolidation Block HR2:

Day 1-5: Dexamethasone 20mg/m2 oral or IV

Days 1,6: Vindesine 3mg/m2 IV

Day 1: Methotrexate 5,000mg/m2 IV

Days 2-4: Ifosfamide 800mg/m2 IV

Days 6: L-Asparaginase 25,000 IU/m2 IM

Day 5: Daunorubicin 30mg/m2 IV

Day 1: Methotrexate 12mg intrathecal

Day 1: Cytarabine 30mg intrathecal

Day 1: Prednisone 10mg intrathecal

Days 6-20: Imatinib 300mg/m2 orally.

Consolidation Block HR3:

Days 1-5: Dexamethasone 20mg/m2 oral or IV

Days 1-2: Cytarabine 2,000mg/m2 IV

Days 3-5: Vepeside 100mg/m2 IV

Day 6: L-Asparaginase 25,000 IU/m2 IM

Day 1: Methotrexate 12mg intrathecal

Day 1: Cytarabine 30mg intrathecal

Day 1: Prednisone 10mg intrathecal

Days 6-20: Imatinib 300mg/m2 orally.

Reinduction Protocol II:

Days 1-21 + tapering: Dexamethasone 10mg/m2 orally

Days 8,15,22,29: Vincristine 1.5mg/m2 IV

Days 8,15,22,29: Doxorubicin 25mg/m2 IV

Days 8,11,15,18: L-Asparaginase 10,000 IU/m2 IM

Day 36: Cyclophosphamide 1,000 mg/m2 IV

Days 36-49: 6-Thioguanine 60mg/m2 orally

Days 38-41, 45-48: Cytarabine 75mg/m2 subcutaneous

Days 38,45: Methotrexate 12mg intrathecal

Days 36-63: Imatinib 300mg/m2 orally.

Interim Maintenance:

Days 1-29: 6-Mercaptopurine 50mg/m2 orally

Days 8,15,22,29: Methotrexate 20mg/m2 orally

With cranial irradiation.

Reinduction Protocol II:

Days 1-21 + tapering: Dexamethasone 10mg/m2 orally

Days 8,15,22,29: Vincristine 1.5mg/m2 IV

Days 8,15,22,29: Doxorubicin 25mg/m2 IV

Days 8,11,15,18: L-Asparaginase 10,000 IU/m2 IM

Day 36: Cyclophosphamide 1,000 mg/m2 IV

Days 36-49: 6-Thioguanine 60mg/m2 orally

Days 38-41, 45-48: Cytarabine 75mg/m2 subcutaneous

Days 36-63: Imatinib 300mg/m2 orally.

Continuation Therapy Maintenance:

6-Mercaptopurine 50mg/m2 orally daily until Day +728 from diagnosis

Methotrexate 20mg/m2 orally weekly until day +728 from diagnosis.

Note: This regimen has also been studied in combination with Dasatinib.

Hyper CVAD with TKI and High-Dose Methotrexate, Cytarabine10-13,e

• Dasatinib-based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4, 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Days 1-14: Dasatinib 100mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-14: Dastinib 100mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

• Imatinib-Based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4, 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Days 1-14: Imatinib 400mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-14: Imatinib 400mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

• Ponatinib-Based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Days 1-14: Ponatinib 45mg orally daily (cycle 1), followed by:

Days 1-21: Ponatinib 30mg orally daily (cycles 2-4).

Repeat cycle every 3 weeks for 4 weeks alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-21: Ponatinib 30mg orally.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

Multiagent Chemotherapy (Daunorubicin, Vincristine, Prednisone, Dexamethasone) + TKI14-16,e

Representative Regimens

• Dasatinib-Based Therapy

Induction Therapy:

Weeks 1-2: All patient received the first 2 weeks of Induction Therapy on a frontline COG or DCFI ALL trial

Weeks 3-4:

Days 1,8 of AALL0622 regimen or Days 15,22 of induction regimen: Vincristine 1.5mg/m2 IV/dose (maximum dose: 2mg)

Days 1,8 of AALL0622 regimen or Days 15,22 of induction regimen: Daunorubicin 25mg/m2 IV/dose

Days 15 of AALL0622 regimen or Day 29 of induction therapy: Triple intrathecal therapy

Note: Patients who were CNS3g also received triple intrathecal therapy on Days 1,8 of AALL0622 regimen or Days 15 and 22 of induction regimen

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Consolidation Therapy – Block I (weeks 6-8)

Days 1-5: Etoposide 100mg/m2 IV

Days 1-5: Ifosfamide 1800mg/m2 with Mesna

Day 1: Triple intrathecal therapy

Note: Prior to study amendment, all patients received dose of triple intrathecal therapy on Day 1, which is Day 36 of protocol therapy. After study amendment, patients did not receive triple intrathecal therapy on Day 1 of consolidation. Patients who were classified as CNS 2a, 2b, or 2cg and those with traumatic taps who did not receive 2 triple intrathecal doses in induction also received doses on Days 8,15.

Consolidation Therapy – Block II

Day 1: High-dose Methotrexate 500mg/m2 over 30 minutes, then 4,500mg/m2 over remainder of 24 hours

Day 1: Triple intrathecal therapy (see note above)

Days 2,3: Cytarabine 3,000mg/m2/dose IV over 3 hours every 12 hours x 4 doses

Beginning on Day 4: Filgrastim (G-CSF) 5mcg/kg/dose subcutaneous/IV continued until ANC >1,500/uL.

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Re-Induction Therapy – Block I (weeks 12-14; patients not proceeding to HSCT):

Days 1,8,15: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1,2: Daunorubicin 45mg/m2 IV

Days 3,4: Cyclophosphamide 250mg/m2 IV every 12 hoursf

Day 4: PEG-Asparaginase 2,500 IU/m2 IM or IV

Day 1,15: Triple intrathecal therapy

Days 1-7, 15-21: Dexamethasone 6mg/m2 orally divided twice daily

Day 5: Filgrastim (G-CSF): 5mcg/kg subcutaneous or IV and continued until ANC >1,500/uL

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Intensification Therapy – Block I (weeks 15-23; patients not proceeding to HSCT):

Days 1,15: High-dose Methotrexate 500mg/m2 IV over 30 minutes, then 4,500mg/m2 over remainder of 24 hours

Day 1,22: Triple intrathecal therapy

Days 22-26: Etoposide 100mg/m2 over 1 hour

Days 22-26: Cyclophosphamide 300mg/m2 IV over 1 houre with Mesna

Day 27: Filgrastim (G-CSF) 5mcg/kg subcutaneous or IV and continued until ANC >1500/uL

Days 43,44: Cytarabine 3,000 mg/m2 IV every 12 hours × 4 doses

Day 44: L-Asparaginase 6,000 IU/m2 administered 6 hours after completion of Cytarabine

Days 1-14, 22-35, 43-56 or Days 1-63: Dasatinib 60mg/m2 orally twice daily.

Re-Induction Therapy – Block II (weeks 24-26; patients not proceeding to HSCT):

Days 1,8,15: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1,2: Daunorubicin 45mg/m2 IV

Days 3,4: Cyclophosphamide 250mg/m2 IV every 12 hours × 4 dosesf

Day 4: PEG-Asparaginase 2,500 IU/m2 IM after last dose of Cyclophosphamide

Days 1,15: Triple intrathecal therapy

Days 1-7, 15-21: Dexamethasone 6mg/m2 orally divided twice daily

Beginning on Day 5: Filgrastim (G-CSF) 5mcg/kg subcutaneous or IV

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Intensification Therapy – Block II (weeks 27-35; patients not proceeding to HSCT):

Days 1,15: High-dose Methotrexate 500mg/m2 IV over 30 minutes, then 4,500mg/m2 over remainder of 24 hours

Day 1,22: Triple intrathecal therapy

Days 22-26: Etoposide 100mg/m2 IV over 1 hour

Days 22-26: Cyclophosphamide 300mg/m2 IV over 1 houre with Mesna

Beginning Day 27: Filgrastim (G-CSF) 5mcg/kg subcutaneous or IV

Days 43,44: Cytarabine 3,000mg/m2 IV every 12 hours x 4 doses

Day 44: L-Asparaginase 6,000 IU/m2 IM given 6 hours after completion of Cytarabine

Days 1-14, 22-35, 43-56 or Days 1-63: Dasatinib 60mg/m2 orally twice daily.

Maintenance Therapy – Cycles 1-4 (weeks 36-67; patients not proceeding to HSCT):

Day 1: High-Dose Methotrexate 500mg/m2 IV over 30 minutes, then 4,500mg/m2 IV over remainder of 24 hours

Day 1,29: Triple intrathecal therapy

Days 1,29: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1-5, 29-33: Dexamethasone 6mg/m2 orally divided twice daily

Days 8-28: Mercaptopurine 75mg/m2 orally

Days 8,15,22: Methotrexate 20mg/m2 orally on an empty stomach

Days 29-33: Etoposide 100mg/m2 IV over 1 hour

Days 29-33: Cyclophosphamide 300mg/m2 IV given immediately following Etoposide with Mesnaf

Beginning on Day 34: Filgrastim (G-CSF) 5mcg/m2 and continued until ANC >1,500/uL

Days 1-14, 29-42 or Days 1-49: Dasatinib 60mg/m2 orally twice daily.

Maintenance Therapy – Cycle 5 (weeks 68-75; patients not proceeding to HSCT):

Beginning on Day 1: Cranial irradiation

Days 1,29: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1-5, 29-33: Dexamethasone 6mg/m2 orally divided twice daily

First Day after Cranial Irradiation Completion: Mercaptopurine 75mg/m2 orally daily

Day 8,15,22,29,36,43,50: Methotrexate 20mg/m2 orally

Days 1-14, 29-42 or Days 1-49: Dasatinib 60mg/m2 orally twice daily.

Maintenance Therapy – Cycles 6-12 (weeks 76-131; patients not proceeding to HSCT)

Days 1,29: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1-5, 29-33: Dexamethasone 6mg/m2 orally divided twice daily

Days 1-56: Mercaptopurine 75mg/m2 orally given on an empty stomach

Days 1,8,15,22,29,36,43,50: Methotrexate 20mg/m2 orally

Days 1-14, 29-42 or Days 1-49 or 1-21: Dasatinib 60mg/m2 orally twice daily.

• Imatinib-Based Therapy

Induction Therapy:

Day 1: Cyclophosphamide 1,200mg/m2 IV over 3 hoursf

Days 1-3: Daunorubicin 60mg/m2 IV over 1 hour

Days 1,8,15,22: Vincristine 1.3mg/m2 IV bolus

Days 1-21: Prednisolone 60mg/m2 orally

Days 8-63: Imatinib 600mg orally

Day 29: Methotrexate 15mg intrathecal

Day 29: Cytarabine 40mg intrathecal

Day 29: Dexamethasone 4mg intrathecal.

Consolidation Therapy – Cycle I:

Day 1: Methotrexate 1,000mg/m2 IV over 24 hours

Days 2,3: Cytarabine 2,000/m2 over 3 hours × 2

Days 1-3: Methylprednisolone 50mg IV over 1 hour × 2

Day 1: Methotrexate 15mg intrathecal

Day 1: Cytarabine 40mg intrathecal

Day 1: Dexamethasone 4mg intrathecal.

Administer for 4 cycles alternating with Cycle II.

Consolidation Therapy – Cycle II:

Days 1-28: Imatinib 600mg orally

Day 1: Methotrexate 15mg intrathecal

Day 1: Cytarabine 40mg intrathecal

Day 1: Dexamethasone 4mg intrathecal.

Administer for 4 cycles alternating with Cycle I.

Maintenance Therapy:

Day 1: Vincristine 1.3mg/m2 IV (bolus) (2mg maximum)

Days 1-5: Prednisolone 60mg/m2 orally

Days 1-28: Imatinib 600mg orally.

Maintenance therapy administered every 4 weeks up to 2 years from the date of CR.

• Nilotinib-Based Therapy

Induction Therapy:

Days 1-3: Daunorubicin 90mg/m2 IV continuous 24 hour infusion

Days 1,8: Vincristine 2mg IV push

Days 1-14: Prednisolone 60mg/m2 orally or 48mg/m2 IV

Day 8 to start of conditioning for allo-HCT or until the end of 2 years of maintenance therapy: Nilotinib 400mg orally twice daily.

Consolidation – Cycle A:

Days 1,2: Daunorubicin 45mg/m2 IV continuous 24-hour infusion

Days 1-8: Vincristine 2mg IV push

Day 1-14: Prednisolone 60mg/m2 orally

Nilotinib 400mg orally twice daily.

Administer for 1 cycle.

Consolidation – Cycle B:

Days 1-4: Cytarabine 2000mg/m2 IV over 2 hours

Days 1-4: Etoposide 150mg/m2 IV over 3 hours

Nilotinib 400mg orally twice daily.

Administer for 2 cycles alternating with Cycle C.

Consolidation – Cycle C:

Days 1-2, 15-16: Methotrexate 220mg/m2 IV bolus, then 60mg/m2 per hour for 36 hours

Leucovorin, followed immediately by 50mg/m2 IV every 6 hours for 3 doses; then Leucovorin orally until serum Methotrexate <0.05 micromol/L

Nilotinib 400mg orally twice daily.

Administer for 2 cycles alternating with Cycle B.

Maintenance Therapy:

Nilotinib 400mg orally twice daily for 2 years.

CNS Prophylaxis:

Up to 10 doses of Methotrexate 15mg intrathecal, with:

Hydrocortisone 50mg during or after Induction Therapy.

Vincristine + Dexamethasone + TKI17

PrePhase Therapy:

Days (-7)-(-1): Prednisone 60mg/m2 orally

Between Days (-7)-(-1): Methotrexate 15mg intrathecal

• Imatinib-Based Regimen

Induction Therapy:

Days 1,8,15,22: Vincristine 2mg IV

Days 1-2, 8-9, 15-16, 22-23: Dexamethasone 40mg orally

Days 1-28: Imatinib 400mg orally twice daily

Note: Induction Therapy with Vincristine + Dexamethasone + Dasatinib and Vincristine + Dexamethasone + Nilotinib are also recommended regimens.

Note: These regimens are used for induction therapy and additional therapy is needed.

Ph (-) Diseaseh

Preferred Regimens

CALGB 10403 (for patients <40 years)18,i

Induction Therapy:

Allopurinol 300mg daily (unless allergic) should be administered until peripheral blasts and extramedullary disease are reduced.

Day 1: Cytarabine 70mg intrathecal

Days 1-28: Prednisone 60mg/m2 daily orally or IV in 2 divided doses

Days 1,8,15,22: Vincristine 1.5mg/m2 IV (maximum dose 2mg)

Days 1,8,15,22: Daunorubicin 25mg/m2 IV

Day 4: Pegylated Asparaginase 2,500 IU/m2 IM or IV

Days 8,29 (also administered on Days 15, 22 for patients with CNS3 g ): Methotrexate 15mg intrathecal.

Extended Remission Induction Therapy (if required):

Days 1-14: Prednisone 60mg/m2 daily orally or IV in 2 divided doses

Day 1: Daunorubicin 25mg/m2 IV

Days 1,8: Vincristine 1.5mg/m2 (maximum dose 2mg) IV

Day 4: Pegylated Asparaginase 2,500 IU/m2 IM or IV.

Remission Consolidation Therapy:

Days 1,29: Cyclophosphamide 1000mg/m2 IV f

Days 1-4,8-11,29-32,36-39: Cytarabine 75mg/m2 IV or SC

Days 1-14,29-42: 6-Mercaptopurine 60mg/m2 orally

Days 15,22,43,50: Vincristine 1.5mg/m2 (maximum 2mg) IV

Days 15,43: Pegylated Asparaginase 2,500 IU/m2 IM or IV

Days 1,8,15,22 (omit doses on Days 15 and 22 for patients with CNS3 g ): Methotrexate 15 mg intrathecal.

Interim Maintenance Therapy:

Days 1,11,21,31,41: Methotrexate at a starting dose of 100mg/m2 IV escalated by 50mg/m2/dose

Days 1,11,21,31,41: Vincristine 1.5mg/m2 IV (maximum dose 2mg)

Days 2,22: Pegylated Asparaginase 2,500 IU/m2 IM or IV

Days 1,31: Methotrexate 15mg intrathecal.

Delayed Intensification Therapy:

Days 1,8,15,43,50: Vincristine 1.5mg/m2 (maximum dose 2mg)

Days 1-7,15-21: Dexamethasone 10mg/m2 orally or IV administered in 2 divided doses

Days 1,,8,15: Doxorubicin 25mg/m2 IV

Days 4 (or Day 5 or Day 6), 43: Pegylated Asparaginase 2,500 IU/m2 IM or IV

Day 29: Cytarabine 1,000mg/m2 IV

Days 29-32, 36-39: Cytarabine 75mg/m2 IV or SC

Days 29-42: 6-Thioguanine 60mg/m2 orally daily

Days 1,29,36: Methotrexate 15mg intrathecal.

Maintenance Therapy:

Days 1,29,57: Vincristine 1.5mg/m2 (maximum dose 2mg) IV

Days 1-5,29-33,57-61: Dexamethasone 6mg/m2 orally daily in 2 divided doses

Days 1-84: 6-Mercaptopurine 75mg/m2 orally daily

Day 1 (and on Day 29 for first course of maintenance): Methotrexate 15mg intrathecal

Days 8,15,22,29,36,43,50,57,64,71,78 (held on Day 29 of the first 4 courses of maintenance with intrathecal Methotrexate is given): Methotrexate 20mg/m2 orally weekly.

COG AALL0232 (for patients ≤21 years)19,20,i

Induction Therapy (for 4 weeks):

Day 0: Cytarabine 15mg intrathecal

Days 1,8,15,22: Vincristine 1.5mg/m2 IV (2mg maximum)

Day 1,8,15,22: Daunorubicin 25mg/m2 IV

Days 1-28: Prednisone 30mg/m2 orally or IV twice daily

Days 4,5, or 6: Pegaspargase 2,500mg/m2 IM i

Note: Patients with CNS3g disease also receive Methotrexate intrathecal on Days 15 and 22.

Extended Induction Therapy (only for patients with M2 disease or M1 disease with >1% minimal residual disease):

Days 8,29 (CNS3g +15,22): Methotrexate 15mg intrathecal

Days 1-14: Prednisone 30mg/m2 orally or IV twice daily

Days 1,8: Vincristine 1.5mg/m2 (2mg maximum) IV

Day 1: Daunorubicin 25mg/m2 IV

Days 4,5, or 6: 2,500 U/m2 Pegaspargase IMi

Consolidation Therapy (for about 7-8 weeks):

Days 1,29: Cyclophosphamide 1,000mg/m2 IV over 30 minutesf

Days 1-4, 8-11, 29-32, 36-39: Cytarabine 75mg/m2

Days 1-14, 29-42: Mercaptopurine 60mg/m2 orally

Days 15,22,43,50: Vincristine 1.5mg IV (2mg maximum)

Days 15,43: Pegaspargase 2,500 U/m2 IM

Days 1,8,15,22: Methotrexate 15mg intrathecal.

Interim Maintenance I:

Days 1,15,29,43: Vincristine 1.5mg/m2 IV (2mg maximum) IV over 24 hours

Days 1,15,29,43: Methotrexate 5,000mg/m2 IV over 24 hours,

Days 1-56: Mercaptopurine 25mg/m2 orally

Days 1,29: Methotrexate 15mg intrathecal

Delayed Intensification I:

Days 1,8,15,43,50: Vincristine 1.5mg/m2 IV (2mg maximum)

Days 4 or 5 or 6, and 43: Pegaspargase 2,500 U/m2 IMi

Days 1-7, 15-21: Dexamethasone 10mg/m2

Days 1,8,15: Doxorubicin 25mg/m2 IV

Days 29-32, 36-39: Cytarabine 75mg/m2

Day 29: Cyclophosphamide 1,000mg/m2 IVf

Days 29-42: Thioguanine 60mg/m2 orally

Days 1,29,36: Methotrexate 15mg intrathecal.

Interim Maintenance II:

Days 1,11,21,31,41: Vincristine 1.5mg/m2 IV

Days 1,11,21,31,41: Methotrexate 100mg/m2 IV

Days 2,22: Pegaspargase 2,500mg/m2 IMi

Days 1,31: Methotrexate 15mg intrathecal.

Delayed Intensification II:

Same regimen as Delayed Intensification I.

Maintenance Therapy:

Days 1,29.57: Vincristine 1.5mg/m2 (2mg maximum) IV

Days 1-5, 29-33, 57-61: Prednisone 20mg/m2 twice daily

Daily: Mercaptopurine 75mg/m2 orally

Weekly: Methotrexate 20mg/m2 orally

Days 1 (and 29 first 4 cycles): Methotrexate 15mg intrathecal.

COG AALL0434 (with Nelarabine added to Consolidation Regimen)21,22,i (for patients with T-ALL)

Induction Therapy:

At diagnostic lumbar puncture or Day 1: Cytarabine 15mg intrathecal

Days 1,8,15,22: Vincristine 1.5mg/m2 IV (2 mg maximum)

Days 1-28: Prednisone 30mg/m2 IV twice daily

Days 1,8,16,22: Daunorubicin 25mg/m2 IV

Days 4,5, or 6: Pegasparagase 2,500 U/m2 IMi

Days 8,29 (CNS3g + Days 15,22): Methotrexate 15mg intrathecal.

Consolidation Therapy With Nelarabine:

Days 8,50: Cyclophosphamide 1,000mg/m2 IVf

Days 8-11, 15-18, 50-53, 57-60: Cytarabine 75mg/m2

Days 8-21, 50-63: Mercaptopurine 60mg/m2

Days 22,29,64,71: Vincristine 1.5mg/m2 IV (2mg maximum)

Days 22,64: Pegaspargase 2,500 U/m2 IMi

Days 15,22,57,64 (omit Day 22 for CNS3 g): Methotrexate 15mg intrathecal

Days 1-5, 43-47: Nelarabine 650mg/m2 IV, with:

Cranial radiation therapy and testicular radiation therapy.

Interim Maintenance:

Days 1,11,21,31,41 (every 10 days x 5 doses): Vincristine 1.5mg/m2 IV (2 mg maximum)

Days 1,11,21,31,41 (every 10 days x 5 doses): Methotrexate 100mg/m2 IV

Days 2,22: Pegaspargase 2,500 U/m2 IMi

Days 1,31: Methotrexate 15mg intrathecal.

Delayed Intensitification without Nelarabine:

Days 1,8,15,43,50: Vincristine 1.5mg/m2 IV (2mg maximum)

Days 4 or 5 or 6, 43: Pegaspargase 2,500 U/m2 IMi

Days 1-7,15-21: Dexamethasone 5mg/m2 twice daily

Days 1,8,15: Doxorubicin 25mg/m2 IV

Days 29-32, 36-39: Cytarabine 75mg/m2

Day 29: 1,000mg Cyclophophamide 1,000mg/m2 IVf

Days 29-42 (omit for patients receiving cranial irradiation therapy): Thioguanine 60mg/m2

Days 1,29,36: Methotrexate 15mg intrathecal.

Delayed Intensification with Nelarabine:

Days 1,8,15,50: Vincristine 1.5mg/m2 IV (2mg maximum)

Days 4 or 5 or 6 and 50: Pegaspargase 2,500 U/m2 IMi

Days 1-7, 15-21: Dexamethasone 5mg/m2 twice daily

Days 1,8,15: Doxorubicin 25mg/m2 IV

Days 36-39, 43-46: Cytarabine 75mg/m2 IV

Day 36: Cyclophosphamide 1,000 mg/m2 IVf

Days 36-49 (omit for patients receiving cranial irradiation therapy): Thioguanine 60mg/m2 IV

Days 1,36,43: Methotrexate 15mg intrathecal

(Days 29-33: Nelarabine 650 mg/m2 IV), with:

Cranial irradiation therapy.

Maintenance Therapy without Nelarabine (12-week cycles):

Days 1,29,57: Vincristine 1.5mg/m2 IV (2mg maximum)

Days 1-5, 29-33, 57-61: Prednisone 20mg/m2 twice daily

Days 1-84: Mercaptopurine 75mg/m2 orally daily

Days 8,15,22,36,43,50,52,64,71: Methotrexate 20mg/m2 orally

Day 1 (and Day 29 first 4 cycles; low-risk only): Methotrexate 15mg intrathecal.

Maintenance Therapy with Nelarabine (12-week cycles):

Days 1,57: Vincristine 1.5mg/m2 IV (2mg maximum)

Days 1-5, 29-33, 57-61: Prednisone 20mg/m2 twice daily

Days 1-28, 36-84: Mercaptopurine 75mg/m2 orally daily

Day 1: Methotrexate 15mg intrathecal

Days 29-33 (first 3 cycles): Nelarabine 650mg/m2 IV

DFCI ALL (study performed in patients <50 years)23,i

Induction Therapy (4 weeks):

Days 1,8,15,22: Vincristine 2mg IV

Days 1-28: Prednisone 40mg/m2

Days 1,2: Doxorubicin 30mg/m2 IV

Day 3: Methotrexate 4g/m2 (8-24 hours after Doxorubicin) with Leucovorin rescue

Day 5: E. coli L-Asparaginase 25,000 IU/m2 IM

Day 0: Cytarabine 50mg intrathecal (prior to initiation of systemic therapy)

Days 15,29: Methotrexate 12mg intrathecal

Days 15,29: Cytarabine 40mg intrathecal

Days 15,29: Hydrocortisone 50mg intrathecal.

CNS Therapy (3 Weeks):

Vincristine 2mg IV x 1 dose

6-Mercaptopurine 50mg/m2 orally x 14 consecutive days

Doxorubicin 30mg/m2 IV x 1 dose

Methotrexate 12mg intrathecal twice weekly x 4 doses

Cytarabine 40mg intrathecal twice weekly x 4 doses, with:

Cranial irradiation.

Intensification (30 weeks; every 3-week cycles):

Day 1: Vincristine 2mg IV

Days 1-5: Dexamethasone 18mg/m2/day orally twice daily

Day 1 of each cycle to a cumulative dose of 300mg/m2

Day 1: Doxorubicin 30mg/m2 IV

6-Mercaptopurine 50mg/m2/day orally × 14 consecutive days

E. coli Asparaginase: Individualized dosing: 12,500 IU/m2/dose (starting dose)

Methotrexate 30mg/m2 IV or IM weekly, 1 day after asparaginase (no weekly Methotrexate until Doxorubicin completed)

At start of cycle: Methotrexate 12mg intrathecal; Cytarabine 40mg intrathecal; Hydrocortisone 50mg intrathecal every 18 weeks.

Note: Intrathecal therapy of Methotrexate/Cytarabine at start of cycle every 18 weeks.

Continuation Therapy (74 weeks; every 3-week cycles):

Same as intensification except no Asparaginase and Dexamethasone dose reduced to 6mg/m2/day.

GRAALL-2005 (for patients <60 years, with Rituximab for CD20-positive disease)24,i

Rituximab (375mg/m2 IV):

Days 1,7: First induction course

Days 1,7: Salvage Reinduction (if needed)

Days 1,29: Consolidation Phase I, II, III

Days 1,7: Late Intensification

Day 1 of Months 1,3,5,7,9,11 of Maintenance Therapy

Prephase Treatment:

Days (-7)-(-1): Prednisone 60mg/m2 orally

Between Days (-7) and (-4): Methotrexate 15mg intrathecal.

Induction Therapy:

Days 1-14: Prednisone 60mg/m2 orally

Days 1,8,15,22: Vincristine 2 mg IV

Days 1-3: Daunorubicin 50mg/m2 IV

Days 15,16: Daunorubicin 30mg/m2 IV

Days 8,10,12: L-Asparaginase 6,000 IU/m2 daily IV over 1 hour (not done if CNS involvement), then,

Days 20,22,24,26,28: L-Asparaginase 6,000 IU/m2 daily IV over 1 hour

Day 1: Cyclophosphamide 750mg/m2 IV over 3 hoursf

Day 15: Cyclophosphamide 750mg/m2 IV over 3 hours (1 infusion) OR Days 15-17: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours (6 infusions)f

Day 18 to neutrophil recovery: Lenograstim 263 mcg/day subcutaneous or IV.

Salvage Reintroduction Therapy:

Days 1-3: Idarubicin 12mg/m2 IV over 1 hour

Days 1-4 (8 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Day 9 to neurotrophil recovery: Lenograstim 263 mcg subcutaneous or IV daily.

Interphase-1 Therapy:

Day 1: Vincristine 2mg IV

Day 1: Dexamethasone 40mg orally daily.

Consolidation Therapy I – Block 1:

Days 1,2 (4 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Days 1,2: Dexamethasone 10mg orally every 12 hours

Day 3: L-Asparaginase (E coli): 10,000 IU/m2 IV over 1 hour

Days 9-13: Lenograstim 263 mcg orally or IV

Consolidation Therapy I – Block 2:

Day 15: Vincristine 2mg IV

Day 15: Methotrexate 3,000 mg/m2 continuous IV over 24 hours

Day 16: L-Asparaginase 10,000 IU/m2 IV over 1 hour

Day 15-21: 6-Methotrexate 60mg/m2 orally

Days 23-27: Lenograstim 263 mcg SC or IV daily

Consolidation Therapy I – Block 3:

Day 29: Methotrexate 25mg/m2 IV

Days 29,30: Cyclophosphamide 500mg/m2 IV daily over 3 hoursf

Days 28,30: Etoposide 75mg/m2 IV over 1 hour.

Day 31 to neutrophil recovery: Lenograstim 263mcg SC or IV daily.

Consolidation Therapy II:

Block 4 – identical to Block 1

Block 5 – identical to Block 2

Block 6 – identical to Block 3

Late Intensification Therapy (if CR after 1st course):

Day 1-14: Prednisone 60mg/m2 orally

Day 1,8,15,22: Vincristine 2mg IV

Day 1-3, 15,16: Daunorubicin 30mg/m2 IV

Day 8,10,12,20,22,24,26,28: L-Asparaginase 6,000 IU/m2 IV over 1 hour

Day 1: Cyclophosphamide 750mg/m2 IV over 3 hours, then,

Day 15 (1 infusion): Cyclophosphamide 750mg/m2 over 3 hours OR Days 15-17 (6 infusions): 300mg/m2 over 3 hours every 12 hourse

Day 18 to neutrophil recovery: Lenograstim 263mcg subcutaneous or IV daily.

Late Intensification Therapy (if late CR):

Days 1-3: Idarubicin 9mg/m2 IV over 1 hour daily

Days1-4 (8 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Day 9 to neutrophil recovery: Lenograstim 263mcg SC or IV daily.

Consolidation Therapy III:

Repeat Consolidation Therapy I Blocks 1-3.

Maintenance Therapy

Day 1 (month 1-12): Vincristine 2mg IV

Days 1-7 (month 1-12): Prednisone 40mg/m2 orally daily

Months 1-24: 6-Mercaptopurine 60mg/m2 orally daily

Months 1-24: Methotrexate 25mg/m2 orally weekly.

Hyper CVAD high-dose Methotrexate/ Cytarabine10,11

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Repeat every 3 weeks for 4 cycles alternating with Cycle A.

Hyper CVAD + Rituximab – high dose Methotrexate/ Cytarabine (for patients with CD20-positive disease)10,11

Cycle A:

Day 1: Rituximab 375mg/m2 IV

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4, 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Repeat every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Rituximab 375mg/m2 IV

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Repeat every 3 weeks for 4 cycles alternating with Cycle A.

Linker Regimen26,27

Induction Therapy (1A):

Days 1-3: Daunorubicin 60mg/m2 IV push, followed by:

Day 15: Daunorubicin 60mg/m2 IV push (only if Day 14 bone marrow has residual leukemia)

Days 1,8,15,22: Vincristine 1.4mg/m2 IV (maximum 2mg if age >40 years) over 5-10 minutes

Days 1-28: Prednisone 60mg/m2 orally

Days 1-4,15-18: Dexamethasone 9mg/m2 orally twice daily

Day 15: Pegaspargase 2,000 international units/m2 (maximum 3,750 international units, rounded to vial size) IV over 1 hour

Day 1: Methotrexate 12mg intrathecal.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (1B):

Days 1-4: Cytarabine 2,000 mg/m2 IV over 2 hours

Days 1-4: Etoposide 500mg/m2 IV over 3 hours

Days 1,8,15: Methotrexate 12mg intrathecal.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (1C):

Days 1,15: Methotrexate 220mg/m2 IV over 15 minutes, then immediately followed by 60mg/m2/hour IV continuous infusion over 36 hours (Alkaline hydration required for high-dose Methotrexate.)

Days 2, 16: Leucovorin 50mg/m2 IV over 15 minutes every 6 hours for 3 doses starting immediately after completion of 36-hour Methotrexate infusion on days 2 and 16, then, Leucovorin 25mg IV over 15 minutes or orally every 6 hours (until Methotrexate serum concentration is <0.05micromol.)

Days 1-28: Mercaptopurine 75mg/m2 orally daily

Days 1, 8: Methotrexate 12mg intrathecal (after adequate clearance of serum Methotrexate).

Administer for one 4-week cycle, followed by:

Consolidation Therapy (2A):

Days 1-3: Daunorubicin 60mg/m2 IV push

Days 1,8,15: Vincristine 1.4mg/m2 (maximum 2mg if age >40 years) IV over 5-10 minutes

Days 1-21: Prednisone 60mg/m2 orally daily OR Days 1-4,15-18: Dexamethasone 9mg/m2 orally twice daily

Day 4: Pegaspargase 2,000 international units/m2, followed by:

Consolidation Therapy (2B):

Days 1-4: Cytarabine 2,000 mg/m2 IV over 2 hours

Days 1-4: Etoposide 500mg/m2 IV over 3 hours

Days 1,8,15: Methotrexate 12mg intrathecal.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (2C):

Days 1,15: Methotrexate 220mg/m2 IV over 15 minutes, then immediately followed by 60mg/m2/hour IV continuous infusion over 36 hours (Alkaline hydration required for high-dose Methotrexate.)

Days 2, 16: Leucovorin 50mg/m2 IV over 15 minutes every 6 hours for 3 doses starting immediately after completion of 36-hour Methotrexate infusion on days 2 and 16, then, Leucovorin 25mg IV over 15 minutes or orally every 6 hours (until Methotrexate serum concentration is <0.05micromol.)

Days 1-28: Mercaptopurine 75mg/m2 orally daily.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (3C):

Days 1,15: Methotrexate 220mg/m2 IV over 15 minutes, then immediately followed by 60mg/m2/hour IV continuous infusion over 36 hours (Alkaline hydration required for high-dose Methotrexate.)

Days 2, 16: Leucovorin 50mg/m2 IV over 15 minutes every 6 hours for 3 doses starting immediately after completion of 36-hour Methotrexate infusion on days 2 and 16, then, Leucovorin 25mg IV over 15 minutes or orally every 6 hours (until Methotrexate serum concentration is <0.05micromol.)

Days 1-28: Mercaptopurine 75mg/m2 orally daily

Administer for one 4-week cycle, followed by:

Maintenance Therapy:

Days 1-28: Mercaptopurine 75mg/m2 orally

Days 1,8,15,22: Methotrexate 20mg/m2 orally.

Repeat cycle every 4 weeks until patient is in complete remission for 30 months.

PETHEMA ALL-96 (patients aged <30 years)28,i

Remission Induction Therapy:

Days 1,8,15,22: Vincristine 2mg IV

Days 1,8,15,22: Daunorubicin 30mg/m2 IV

Days 1-27: Prednisone 60mg/m2 IV or orally daily

Days 28-35: Prednisone 30mg/m2 IV or orally daily

Days 10-12, 17-19, 24-26: Asparaginase 10,000 U/m2 IV

Day 36: Cyclophosphamide 1,000mg/m2 IVf

Days 1,29: Methotrexate 15mg intrathecal

Days 1,29: Cytarabine 30mg intrathecal

Days 1,29: Hydrocortisone 20mg intrathecal

Consolidation Therapy I:

Days 1-7: Mercaptopurine 50mg/m2 orally

Days 1,28,56: Methotrexate 3,000mg/m2 (with folinic acid rescue, beginning 12 hours after the end of Methotrexate infusion) IV over 24 hours

Days 14,42: Teniposide 150mg/m2 IV every 12 hours

Days 14-15,42-43: Cytarabine 500mg/m2 every 12 hours

Days 1,28,56: Methotrexate 15mg intrathecal

Days 1,28,56: Cytarabine 30mg intrathecal

Days 1,28,56: Hydrocortisone 20mg intrathecal

Consolidation Therapy II/Reinduction:

Days 1-14: Dexamethasone 10mg/m2 orally or IV daily

Days 15-21: Dexamethasone 5mg/m2 orally or IV daily

Days 1,8,15: Vincristine 1.5mg/m2 IV (maximum 2mg)

Days 1,2,8,9: Daunorubicin 30mg/m2 IV

Days 1,15: Cyclophosphamide 600mg/m2 IV dailyf

Days 1-3, 15-17: Asparaginase 10,000 U/m2 IM or IV

Days 1,15: Methotrexate 15mg intrathecal

Days 1,15: Cytarabine 30mg intrathecal

Days 1,15: Hydrocortisone 20mg intrathecal

Maintenance Therapy I (+ Reinductions until week 52):

Methotrexate 20mg/m2 IM weekly

Mercaptopurine 50mg/m2 orally daily.

Reinductions (every 4 weeks):

Day 1: Vincristine 1.5 mg/m2 IV (maximum 2mg)

Days 1-7: Prednisone 60mg/m2 IV or orally daily

Day 1: Asparaginase 20,000 U/m2 IV

Day 1: Methotrexate 15mg intrathecal

Day 1: Cytarabine 30mg intrathecal

Day 1: Hydrocortisone 20mg intrathecal

Maintenance Therapy II (weeks 53-104):

Methotrexate 20mg/m2 IM weekly

Mercaptopurine 50mg/m2 orally daily.

USC ALL Based on CCG-1882 (for patients aged 18-57 years)27

Induction Therapy I:

Days 1-3: Daunorubicin 60mg/m2 IV

Days 1,8,15,22: Vincristine 1.4mg/m2 IV (maximum, 2mg)

Day 15: Pegaspargase 2,000 IU/m2 IV

Days 1-28: Prednisone 60mg/m2 orally

Days 8,15: Methotrexate 12mg intrathecal.

Induction Therapy II:

Days 1,29: Cyclophosphamide 1,000mg/m2 IVf

Days 1-4, 8-11, 29-32, 36-39: Cytarabine 75mg/m2 IV

Days 15,22,43,50: Vincristine 1.4mg/m2 IV (maximum, 2mg)

Day 15: Pegasparagase 2,000 IU/m2 IV

Days 15-29: Prednisone 20mg/m2 orally

Days 1-14, 29-43: Mercaptopurine 60mg/m2 orally

Days 1,8,15,22: Methotrexate 12mg intrathecal.

Intensification Therapy:

Days 1, 15: Methotrexate 1,000mg/m2 IV (T-cell ALL, 2,500mg/m2 IV), with Leucovorin 15mg every 6 hours IV starting 36 hours from start of Methotrexate

Day 16: Pegaspargase 2,000 IU/m2 IV

Days 16-30: Prednisone 20mg/m2 orally.

Consolidation Therapy:

Days 1-5: Cytarabine 75mg/m2 IV

Days 1-5: Teniposide 60mg/m2 IV.

Delayed Reinduction Therapy:

Days 1,8,15: Daunorubicin 25mg/m2 IV

Days 1,8,15,43,50: Vincristine 1.4mg/m2 IV (maximum, 2mg)

Days 15-22, 43-50: Dexamethasone 10mg/m2 orally

Day 15: Pegasparagase 2,000 IU/m2 IV

Day 29: Cyclophosphamide 1,000mg/m2 IVf

Days 29-32, 36-39: Cytarabine 75mg/m2 IV

Days 26-42: Thioguanine 60mg/m2 orally

Days 1,29,36: Methotrexate 12mg intrathecal.

Maintenance Therapy

Days 1-5 (year 1, monthly; year 2, every 2 months): Prednisone 60mg/m2 IV orally

Day 1 (year 1, monthly; year 2, every 2 months): Vincristine 1.4mg/m2 IV (maximum, 2mg)

Days 1-28: Mercaptopurine 60mg/m2 orally

Days 1,8,15,22: Methotrexate 20mg/m2 orally

Once every 3 months (year 1): Methotrexate 12mg intrathecal.

Adults (age 40-64 years, unless otherwise specified)c

Ph (+) Diseasec

Other Recommended Regimens

CALGB 107015,e

Course I (First Induction):

Days 1-7: Dasatinib 140mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV

Course II (If ≤20% lymphoblasts in marrow at Day 15):

Days 1-7: Dasatinib 140mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV.

Course II (If >20% lymphoblasts in marrow at Day 15):

Days 1-7: Dasatinib 140 mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV.

Vincristine and Daunorubicin also administered.

Course III (Second Induction for patients not in CR/CRi :

Patients received Dasatinib, Cyclophosphamide, Vincristine, Daunarubicin, Dexamethasone.

Course IV (CNS Prophylaxis):

Patients received Dasatinib, IV Vincristine, and IV, oral, and intrathecal Methotrexate.

Course V :

Patients treated with stem cell transplantation or chemotherapy.

Course VI (Maintenance):

Dasatinib

Starting on Day 30 of Course V and continued for 12 months and until 2 consecutive negative BCR-ABL1 RT-PCR assays 3 months apart or relapse.

Corticosteroids + TKI6,7,d

• Dasatinib + Prednisone

PrePhase:

Days (-7-[-1]): Prednisone 10-60mg/m2 in increasing doses.

Induction Therapy:

Dasatinib 70mg twice daily for 84 days

Prednisone 60mg/m2 daily (capped at 120mg daily) administered until Day 24 and then tapered and stopped at Day 32.

Days 22,43: Methotrexate intrathecal.

• Imatinib + Prednisone

PrePhase:

Days (-7-[-1]): Prednisone 10-40mg/m2 in increasing doses from 10-40mg/m2.

Induction Therapy:

Days 1-45: Imatinib 800mg orally

Days 1-45: Prednisone 40mg/m2

Note: Induction Therapy with Corticosteroid + Nilotinib is also a recommended regimen.

Note: These regimens are used for induction therapy and additional therapy is needed.

Hyper CVAD with TKI and High-Dose Methotrexate/ Cytarabine10-13,d

• Dasatinib-based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Days 1-14: Dasatinib 100mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-14: Dastinib 100mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

• Imatinib-Based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-14: Imatinib 400mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-14: Imatinib 400mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

• Ponatinib-Based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Days 1-14: Ponatinib 45mg orally daily (cycle 1), followed by:

Days 1-21: Ponatinib 30mg orally daily (cycles 2-4).

Repeat cycle every 3 weeks for 4 weeks alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-21: Ponatinib 30mg orally.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

Multiagent Chemotherapy (Daunorubicin, Vincristine, Prednisone, Dexamethasone) + TKI14-16,d

Representative Regimens

• Dasatinib-Based Therapy

Induction Therapy:

Weeks 1-2: All patient received the first 2 weeks of Induction Therapy on a frontline COG or DCFI ALL trial

Weeks 3-4:

Days 1,8 of AALL0622 regimen OR Days 15,22 of induction regimen: Vincristine 1.5mg/m2 IV/dose (maximum dose: 2mg)

Days 1,8 of AALL0622 regimen OR Days 15,22 of induction regimen: Daunorubicin 25mg/m2 IV/dose

Days 15 of AALL0622 regimen OR Day 29 of induction therapy: Triple intrathecal therapy

Note: Patients who were CNS3g also received triple intrathecal therapy on Days 1,8 of AALL0622 regimen or Days 15 and 22 of induction regimen

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Consolidation Therapy – Block I (weeks 6-8)

Days 1-5: Etoposide 100mg/m2 IV

Days 1-5: Ifosfamide 1800mg/m2 with Mesna

Day 1: Triple intrathecal therapy

Note: Prior to study amendment, all patients received dose of triple intrathecal therapy on Day 1, which is Day 36 of protocol therapy. After study amendment, patients did not receive triple intrathecal therapy on Day 1 of consolidation. Patients who were classified as CNS 2a, 2b, or 2cg and those with traumatic taps who did not receive 2 triple intrathecal doses in induction also received doses on Days 8,15.

Consolidation Therapy – Block II

Day 1: High-dose Methotrexate 500mg/m2 over 30 minutes, then 4,500mg/m2 over remainder of 24 hours

Day 1: Triple intrathecal therapy (see note above)

Days 2,3: Cytarabine 3,000mg/m2/dose IV over 3 hours every 12 hours × 4 doses

Beginning on Day 4: Filgrastim (G-CSF) 5mcg/kg/dose subcutaneous/IV continued until ANC >1,500/uL.

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Re-Induction Therapy – Block I (weeks 12-14; patients not proceeding to HSCT):

Days 1,8,15: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1,2: Daunorubicin 45mg/m2 IV

Days 3,4: Cyclophosphamide 250mg/m2 IV every 12 hoursf

Day 4: PEG-Asparaginase 2,500 IU/m2 IM or IV

Day 1,15: Triple intrathecal therapy

Days 1-7, 15-21: Dexamethasone 6mg/m2 orally divided twice daily

Day 5: Filgrastim (G-CSF): 5mcg/kg subcutaneous or IV and continued until ANC >1,500/uL

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Intensification Therapy – Block I (weeks 15-23; patients not proceeding to HSCT):

Days 1,15: High-dose Methotrexate 500mg/m2 IV over 30 minutes, then 4,500mg/m2 over remainder of 24 hours

Day 1,22: Triple intrathecal therapy

Days 22-26: Etoposide 100mg/m2 over 1 hour

Days 22-26: Cyclophosphamide 300mg/m2 IV over 1 hour with Mesnaf

Day 27: Filgrastim (G-CSF) 5mcg/kg subcutaneous or IV and continued until ANC >1500/uL

Days 43,44: Cytarabine 3,000 mg/m2 IV every 12 hours × 4 doses

Day 44: L-Asparaginase 6,000 IU/m2 administered 6 hours after completion of Cytarabine

Days 1-14, 22-35, 43-56 or Days 1-63: Dasatinib 60mg/m2 orally twice daily.

Re-Induction Therapy – Block II (weeks 24-26; patients not proceeding to HSCT):

Days 1,8,15: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1,2: Daunorubicin 45mg/m2 IV

Days 3,4: Cyclophosphamide 250mg/m2 IV every 12 hours × 4 doses

Day 4: PEG-Asparaginase 2,500 IU/m2 IM after last dose of Cyclophosphamidef

Days 1,15: Triple intrathecal therapy

Days 1-7, 15-21: Dexamethasone 6mg/m2 orally divided twice daily

Beginning on Day 5: Filgrastim (G-CSF) 5mcg/kg subcutaneous or IV

Days 1-14 or 1-21: Dasatinib 60mg/m2 orally twice daily.

Intensification Therapy – Block II (weeks 27-35; patients not proceeding to HSCT):

Days 1,15: High-dose Methotrexate 500mg/m2 IV over 30 minutes, then 4,500mg/m2 over remainder of 24 hours

Day 1,22: Triple intrathecal therapy

Days 22-26: Etoposide 100mg/m2 IV over 1 hour

Days 22-26: Cyclophosphamide 300mg/m2 IV over 1 hour with Mesnaf

Beginning Day 27: Filgrastim (G-CSF) 5mcg/kg subcutaneous or IV

Days 43,44: Cytarabine 3,000mg/m2 IV every 12 hours × 4 doses

Day 44: L-Asparaginase 6,000 IU/m2 IM given 6 hours after completion of Cytarabine

Days 1-14, 22-35, 43-56 or Days 1-63: Dasatinib 60mg/m2 orally twice daily.

Maintenance Therapy – Cycles 1-4 (weeks 36-67; patients not proceeding to HSCT):

Day 1: High-Dose Methotrexate 500mg/m2 IV over 30 minutes, then 4,500mg/m2 IV over remainder of 24 hours

Day 1,29: Triple intrathecal therapy

Days 1,29: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1-5, 29-33: Dexamethasone 6mg/m2 orally divided twice daily

Days 8-28: Mercaptopurine 75mg/m2 orally

Days 8,15,22: Methotrexate 20mg/m2 orally on an empty stomach

Days 29-33: Etoposide 100mg/m2 IV over 1 hour

Days 29-33: Cyclophosphamide 300mg/m2 IV given immediately following Etoposide with Mesnaf

Beginning on Day 34: Filgrastim (G-CSF) 5mcg/m2 and continued until ANC >1,500/uL

Days 1-14, 29-42 or Days 1-49: Dasatinib 60mg/m2 orally twice daily.

Maintenance Therapy – Cycle 5 (weeks 68-75; patients not proceeding to HSCT):

Beginning on Day 1: Cranial irradiation

Days 1,29: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1-5, 29-33: Dexamethasone 6mg/m2 orally divided twice daily

First Day after Cranial Irradiation Completion: Mercaptopurine 75mg/m2 orally daily

Day 8,15,22,29,36,43,50: Methotrexate 20mg/m2 orally

Days 1-14, 29-42 or Days 1-49: Dasatinib 60mg/m2 orally twice daily.

Maintenance Therapy – Cycles 6-12 (weeks 76-131; patients not proceeding to HSCT)

Days 1,29: Vincristine 1.5mg/m2 IV (maximum dose: 2mg)

Days 1-5, 29-33: Dexamethasone 6mg/m2 orally divided twice daily

Days 1-56: Mercaptopurine 75mg/m2 orally given on an empty stomach

Days 1,8,15,22,29,36,43,50: Methotrexate 20mg/m2 orally

Days 1-14, 29-42 or Days 1-49 or 1-21: Dasatinib 60mg/m2 orally twice daily.

• Imatinib-Based Therapy

Induction Therapy:

Day 1: Cyclophosphamide 1,200mg/m2 IV over 3 hoursf

Days 1-3: Daunorubicin 60mg/m2 IV over 1 hour

Days 1,8,15,22: Vincristine 1.3mg/m2 IV bolus

Days 1-21: Prednisolone 60mg/m2 orally

Days 8-63: Imatinib 600mg orally

Day 29: Methotrexate 15mg intrathecal

Day 29: Cytarabine 40mg intrathecal

Day 29: Dexamethasone 4mg intrathecal.

Consolidation Therapy – Cycle I:

Day 1: Methotrexate 1,000mg/m2 IV over 24 hours

Days 2,3: Cytarabine 2,000/m2 over 3 hours × 2

Days 1-3: Methylprednisolone 50mg IV over 1 hour × 2

Day 1: Methotrexate 15mg intrathecal

Day 1: Cytarabine 40mg intrathecal

Day 1: Dexamethasone 4mg intrathecal.

Administer for 4 cycles alternating with Cycle II.

Consolidation Therapy – Cycle II:

Days 1-28: Imatinib 600mg orally

Day 1: Methotrexate 15mg intrathecal

Day 1: Cytarabine 40mg intrathecal

Day 1: Dexamethasone 4mg intrathecal.

Administer for 4 cycles alternating with Cycle I.

Maintenance Therapy:

Day 1: Vincristine 1.3mg/m2 IV (bolus) (2mg maximum)

Days 1-5: Prednisolone 60mg/m2 orally

Days 1-28: Imatinib 600mg orally.

Maintenance therapy administered every 4 weeks up to 2 years from the date of CR.

• Nilotinib-Based Therapy

Induction Therapy:

Days 1-3: Daunorubicin 90mg/m2 IV continuous 24 hour infusion

Days 1,8: Vincristine 2mg IV push

Days 1-14: Prednisolone 60mg/m2 orally or 48mg/m2 IV

Day 8 to start of conditioning for allo-HCT or until the end of 2 years of maintenance therapy: Nilotinib 400mg orally twice daily.

Consolidation – Cycle A:

Days 1,2: Daunorubicin 45mg/m2 IV continuous 24-hour infusion

Days 1-8: Vincristine 2mg IV push

Days 1-14: Prednisolone 60mg/m2 orally

Nilotinib 400mg orally twice daily.

Administer for 1 cycle.

Consolidation – Cycle B:

Days 1-4: Cytarabine 2000mg/m2 IV over 2 hours

Days 1-4: Etoposide 150mg/m2 IV over 3 hours

Nilotinib 400mg orally twice daily.

Administer for 2 cycles alternating with Cycle C.

Consolidation – Cycle C:

Days 1-2, 15-16: Methotrexate 220mg/m2 IV bolus, then 60mg/m2 per hour for 36 hours

Leucovorin, followed immediately by 50mg/m2 IV every 6 hours for 3 doses; then Leucovorin orally until serum Methotrexate <0.05micromol/L

Nilotinib 400mg orally twice daily.

Administer for 2 cycles alternating with Cycle B.

Maintenance Therapy:

Nilotinib 400mg orally twice daily for 2 years.

CNS Prophylaxis:

Up to 10 doses of Methotrexate 15mg intrathecal, with:

Hydrocortisone 50mg during or after Induction Therapy.

Vincristine + Dexamethasone + TKI17, d

PrePhase Therapy:

Days (-7)-(-1): Prednisone 60mg/m2 orally

Between Days (-7)-(-1): Methotrexate 15mg intrathecal

• Imatinib-Based Regimen

Induction Therapy:

Days 1,8,15,22: Vincristine 2mg IV

Days 1-2, 8-9, 15-16, 22-23: Dexamethasone 40mg orally

Days 1-28: Imatinib 400mg orally twice daily

Note: Induction Therapy with Vincristine + Dexamethasone + Dasatinib and Vincristine + Dexamethasone + Nilotinib are also recommended regimens.

Note: These regimens are used for induction therapy and additional therapy is needed.

Ph (-) Diseaseh

Other Recommended Regimens

CALGB 8811 Larson Regimen27,29

Induction Therapy (patients age <60 years):

Day 1: Cyclophosphamide 1,200g/m2 IV over 30 minutesf

Days 1-3: Daunorubicin 45mg/m2 IV push

Days 1,8,15,22: Vincristine 2mg IV over 5-10 minutes

Days 1-21: Prednisone 60mg/m2 orally daily

Day 5: Pegaspargase 2,000 international units/m2 (maximum 3,750 international units, rounded to vial size) IV over 1 hour.

Administer for one 4-week cycle.

OR

Induction Therapy (patients ≥60 years):

Day 1: Cyclophosphamide 800mg/m2 IV over 30 minutesf

Days 1-3: Daunorubicin 30mg/m2 IV push

Days 1,8,15,22: Vincristine 2mg IV over 5-10 minutes

Days 1-7: Prednisone 60mg/m2 orally daily

Day 5: Pegaspargase 2,000 international units/m2 (maximum 3,750 international units, rounded to vial size) IV over 1 hour.

Administer for one 4-week cycle, followed by:

Early Intensification:

Day 1: Cyclophosphamide 1,000mg/m2 IV over 30 minutesf

Days 1-14: Mercaptopurine 60mg/m2 orally daily

Days 1-4, 8-11: Cytarabine 75mg/m2 subcutaneous

Day 1: Methotrexate 15mg intrathecal

Days 15,22: Vincristine 2mg IV over 5-10 minutes

Day 5: Pegaspargase 2,000 international units/m2 (maximum 3,750 international units, rounded to vial size) IV over 1 hour.

Repeat every 4 weeks for 2 cycles, followed by:

CNS Prophylaxis and Interim Maintenance:

Days 1,8,15,22,29: Methotrexate 15mg intrathecal

Days 1-70: Mercaptopurine 60mg/m2 orally daily

Days 36,43,50,57,64: Methotrexate 20mg/m2 orally daily

Administer for one 84-day cycle with cranial irradiation on days 1-12, followed by:

Late Intensification:

Days 1,8,15: Doxorubicin 30mg/m2 IV push

Days 1,8,15: Vincristine 2mg IV over 5-10 minutes

Days 1-14: Dexamethasone 10mg/m2 orally daily

Day 29: Cyclophosphamide 1,000mg/m2 IV over 30 minutesf

Days 29-42: Thioguanine 60mg/m2 orally daily

Days 29-32, 36-39: Cytarabine 75 mg/m2 subcutaneous daily.

Administer for one 56-day cycle, followed by:

Prolonged Maintenance:

Day 1: Vincristine 2mg IV over 5-10 minutes

Days 1-5: Prednisone 60mg/m2 orally daily

Days 1,8,15,22: Methotrexate 20mg/m2 orally daily

Days 1-28: Mercaptopurine 60mg/m2 orally daily.

Repeat cycle every 4 weeks until 24 months from diagnosis.

Note: For Patients aged 60 years or older, reduced doses of Cyclophosphamide, Daunorubicin, and Prednisone.

GRAALL-2005 (with Rituximab for CD20-Positive Disease) – for patients aged <60 years24

Rituximab (375mg/m2 IV):

Days 1,7: First induction course

Days 1,7: Salvage Reinduction (if needed)

Days 1,29: Consolidation Phase I, II, III

Days 1,7: Late Intensification

Day 1 of Months 1,3,5,7,9,11 of Maintenance Therapy

Prephase Treatment:

Days (-7)-(-1): Prednisone 60mg/m2 orally

Between Days (-7) and (-4): Methotrexate 15mg intrathecal.

Induction Therapy:

Days 1-14: Prednisone 60mg/m2 orally

Days 1,8,15,22: Vincristine 2 mg IV

Days 1-3: Daunorubicin 50mg/m2 IV

Days 15,16: Daunorubicin 30mg/m2 IV

Days 8,10,12: L-Asparaginase 6,000 IU/m2 daily IV over 1 hour (not done if CNS involvement), then,

Days 20,22,24,26,28: L-Asparaginase 6,000 IU/m2 daily IV over 1 hour

Day 1: Cyclophosphamide 750mg/m2 IV over 3 hoursf

Day 15: Cyclophosphamide 750mg/m2 IV over 3 hours (1 infusion) OR Days 15-17: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours (6 infusions)f

Day 18 to neutrophil recovery: Lenograstim 263 mcg/day subcutaneous or IV.

Salvage Reintroduction Therapy:

Days 1-3: Idarubicin 12mg/m2 IV over 1 hour

Days 1-4 (8 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Day 9 to neurotrophil recovery: Lenograstim 263 mcg subcutaneous or IV daily.

Interphase-1 Therapy:

Day 1: Vincristine 2mg IV

Day 1: Dexamethasone 40mg orally daily.

Consolidation Therapy I – Block 1:

Days 1,2 (4 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Days 1,2: Dexamethasone 10mg orally every 12 hours

Day 3: L-Asparaginase (E coli): 10,000 IU/m2 IV over 1 hour

Days 9-13: Lenograstim 263 mcg orally or IV

Consolidation Therapy I – Block 2:

Day 15: Vincristine 2mg IV

Day 15: Methotrexate 3,000 mg/m2 continuous IV over 24 hours

Day 16: L-Asparaginase 10,000 IU/m2 IV over 1 hour

Day 15-21: 6-Methotrexate 60mg/m2 orally

Days 23-27: Lenograstim 263 mcg SC or IV daily

Consolidation Therapy I – Block 3:

Day 29: Methotrexate 25mg/m2 IV

Days 29,30: Cyclophosphamide 500mg/m2 IV daily over 3 hoursf

Days 28,30: Etoposide 75mg/m2 IV over 1 hour.

Day 31 to neutrophil recovery: Lenograstim 263 mcg SC or IV daily.

Consolidation Therapy II:

Block 4 – identical to Block 1

Block 5 – identical to Block 2

Block 6 – identical to Block 3

Late Intensification Therapy (if CR after 1st course):

Day 1-14: Prednisone 60mg/m2 orally

Day 1,8,15,22: Vincristine 2mg IV

Day 1-3, 15,16: Daunorubicin 30mg/m2 IV

Day 8,10,12,20,22,24,26,28: L-Asparaginase 6,000 IU/m2 IV over 1 hour

Day 1: Cyclophosphamide 750mg/m2 IV over 3 hours, then,

Day 15 (1 infusion): Cyclophosphamide 750mg/m2 over 3 hours OR
Days 15-17 (6 infusions): 300mg/m2 over 3 hours every 12 hoursf

Day 18 to neutrophil recovery: Lenograstim 263mcg subcutaneous or IV daily.

Late Intensification Therapy (if late CR):

Days 1-3: Idarubicin 9mg/m2 IV over 1 hour daily

Days 1-4 (8 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Day 9 to neutrophil recovery: Lenograstim 263mcg SC or IV daily.

Consolidation Therapy III:

Repeat Consolidation Therapy I Blocks 1-3.

Maintenance Therapy

Day 1 (month 1-12): Vincristine 2mg IV

Days 1-7 (month 1-12): Prednisone 40mg/m2 orally daily

Months 1-24: 6-Mercaptopurine 60mg/m2 orally daily

Months 1-24: Methotrexate 25mg/m2 orally weekly.

Hyper CVAD high-dose Methotrexate/ Cytarabine10,11

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathechal

Day 7: Cytarabine 100mg intrathecal.

Repeat every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 13 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Repeat every 3 weeks for 4 cycles alternating with Cycle A.

Hyper CVAD + Rituximab – high dose Methotrexate/ Cytarabine [for patients with CD20-positive disease]10,11

Cycle A:

Day 1: Rituximab 375mg/m2 IV

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathechal

Day 7: Cytarabine 100mg intrathecal.

Repeat every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Rituximab 375mg/m2 IV

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine (age <60 years) 3,000mg/m2 IV over 3 hours every 12 hours for 4 doses OR Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Repeat every 3 weeks for 4 cycles alternating with Cycle A.

Linker Regimen (for patients aged <60 years)26,27

Induction Therapy (1A):

Days 1-3: Daunorubicin 60mg/m2 IV push, followed by:

Day 15: Daunorubicin 60mg/m2 IV push (only if Day 14 bone marrow has residual leukemia)

Days 1,8,15,22: Vincristine 1.4mg/m2 IV (maximum 2mg if age >40 years) over 5-10 minutes

Days 1-28: Prednisone 60mg/m2 orally

Days 1-4,15-18: Dexamethasone 9mg/m2 orally twice daily

Day 15: Pegaspargase 2,000 international units/m2 (maximum 3,750 international units, rounded to vial size) IV over 1 hour

Day 1: Methotrexate 12mg intrathecal.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (1B):

Days 1-4: Cytarabine 2,000 mg/m2 IV over 2 hours

Days 1-4: Etoposide 500mg/m2 IV over 3 hours

Days 1,8,15: Methotrexate 12mg intrathecal.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (1C):

Days 1,15: Methotrexate 220mg/m2 IV over 15 minutes, then immediately followed by 60mg/m2/hour IV continuous infusion over 36 hours (Alkaline hydration required for high-dose Methotrexate.)

Days 2,16: Leucovorin 50mg/m2 IV over 15 minutes every 6 hours for 3 doses starting immediately after completion of 36-hour Methotrexate infusion on days 2 and 16, then,

Leucovorin 25mg IV over 15 minutes or orally every 6 hours (until Methotrexate serum concentration is <0.05 micromol.)

Days 1-28: Mercaptopurine 75mg/m2 orally daily

Days 1 8: Methotrexate 12mg intrathecal (after adequate clearance of serum Methotrexate).

Administer for one 4-week cycle, followed by:

Consolidation Therapy (2A):

Days 1-3: Daunorubicin 60mg/m2 IV push

Days 1,8,15: Vincristine 1.4mg/m2 (maximum 2mg if age >40 years) IV over 5-10 minutes

Days 1-21: Prednisone 60mg/m2 orally daily OR Days 1-4,15-18: Dexamethasone 9mg/m2 orally twice daily)

Day 4: Pegaspargase 2,000 international units/m2, followed by:

Consolidation Therapy (2B):

Days 1-4: Cytarabine 2,000 mg/m2 IV over 2 hours

Days 1-4: Etoposide 500mg/m2 IV over 3 hours

Days 1,8,15: Methotrexate 12mg intrathecal.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (2C):

Days 1,15: Methotrexate 220mg/m2 IV over 15 minutes, then immediately followed by 60mg/m2/hour IV continuous infusion over 36 hours (Alkaline hydration required for high-dose Methotrexate.)

Days 2, 16: Leucovorin 50mg/m2 IV over 15 minutes every 6 hours for 3 doses starting immediately after completion of 36-hour Methotrexate infusion on days 2 and 16, then,

Leucovorin 25mg IV over 15 minutes or orally every 6 hours (until Methotrexate serum concentration is <0.05 micromol.)

Days 1-28: Mercaptopurine 75mg/m2 orally daily.

Administer for one 4-week cycle, followed by:

Consolidation Therapy (3C):

Days 1,15: Methotrexate 220mg/m2 IV over 15 minutes, then immediately followed by 60mg/m2/hour IV continuous infusion over 36 hours (Alkaline hydration required for high-dose Methotrexate.)

Days 2, 16: Leucovorin 50mg/m2 IV over 15 minutes every 6 hours for 3 doses starting immediately after completion of 36-hour Methotrexate infusion on days 2 and 16, then,

Leucovorin 25mg IV over 15 minutes or orally every 6 hours (until Methotrexate serum concentration is <0.05 micromol.)

Days 1-28: Mercaptopurine 75mg/m2 orally daily.

Administer for one 4-week cycle, followed by:

Maintenance Therapy:

Days 1-28: Mercaptopurine 75mg/m2 orally

Days 1,8,15,22: Methotrexate 20mg/m2 orally.

Repeat cycle every 4 weeks until patient is in complete remission for 30 months.

Note: Rituximab can be administered with this regimen for patients with CD20-positive diease. Refer to GRAALL-2005 regmen for timing and frequency of administration.

MRC UKALLXII/ ECOG299330

Induction Therapy:

Phase 1, weeks 1-4:

Days 1,8,15,22: Daunorubicin 60mg/m2 IV

Days 1,8,15,22: Vincristine 1.4mg/m2 IV

Days 17-28: L-Asparaginase 10,000 U IV or IM

Days 1-28: Prednisone 60mg/m2 orally daily

Day 15: Methotrexate 12.5mg intrathecal.

Phase 2, weeks 5-8:

Days 1,15,29: Cyclophosphamide 650mg/m2 IVf

Days 1-4,8-11,15-18,22-25: Cytarabine 75mg/m2 IV

Days 1-28: 6-Mercaptopurine 6mg/m2 orally

Days 1,8,15,22: Methotrexate 12.5mg intrathecal.

Older Adults (age ≥65 years, unless otherwise specified) j-o

Ph (+) Disease

Low-Intensity

Corticosteroids + TKI6.7,e

• Dasatinib + Prednisone

PrePhase:

Days (-7-[-1]): Prednisone 10-60mg/m2 in increasing doses.

Induction Therapy:

Dasatinib 70mg twice daily for 84 days

Prednisone 60mg/m2 daily (capped at 120mg daily) administered until Day 24 and then tapered and stopped at Day 32.

Days 22,43: Methotrexate intrathecal.

• Imatinib + Prednisone

PrePhase:

Days (-7-[-1]): Prednisone in increasing doses from 10-40mg/m2.

Induction Therapy:

Days 1-45: Imatinib 800mg orally

Days 1-45: Prednisone 40mg/m2

Note: Induction Therapy with Corticosteroid + Nilotinib is also a recommended regimen.

Note: These regimens are used for induction therapy and additional therapy is needed.

Vincristine + Dexamethasone + TKI17,e

PrePhase Therapy:

Days (-7)-(-1): Prednisone 60mg/m2 orally

Between Days (-7)-(-1): Methotrexate 15mg intrathecal

• Imatinib-Based Regimen

Induction Therapy:

Days 1,8,15,22: Vincristine 2mg IV

Days 1-2, 8-9, 15-16, 22-23: Dexamethasone 40mg orally

Days 1-28: Imatinib 400mg orally twice daily

Note: Induction Therapy with Vincristine + Dexamethasone + Dasatinib and Vincristine + Dexamethasone + Nilotinib are also recommended regimens.

Note: These regimens are used for induction therapy and additional therapy is needed.

Moderate Intensity

CALGB 107015,e

Course I (First Induction):

Days 1-7: Dasatinib 140 mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV

Course II (If ≤20% lymphoblasts in marrow at Day 15):

Days 1-7: Dasatinib 140 mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV.

Course II (If >20% lymphoblasts in marrow at Day 15):

Days 1-7: Dasatinib 140 mg orally daily

Days 1-7: Dexamethasone 10mg/m2 orally or IV.

Vincristine and Daunorubicin also administered.

Course III (Second Induction for patients not in CR/CRi :

Patients received Dasatinib, Cyclophosphamide, Vincristine, Daunarubicin, Dexamethasone.

Course IV (CNS Prophylaxis):

Patients received Dasatinib, IV Vincristine, and IV, oral, and intrathecal Methotrexate.

Course V :

Patients treated with stem cell transplantation or chemotherapy.

Course VI (Maintenance):

Dasatinib

Starting on Day 30 of Course V and continued for 12 months and until 2 consecutive negative BCR-ABL1 RT-PCR assays 3 months apart or relapse.

EWALL31-33,e

• EWALL + Dasatinib (EWALL-Ph-001)

Prephase Period

Days (-7)-(-3): Dexamethasone 10mg daily

Methotrexate 15mg intrathecal administered once.

Induction Therapy:

Days 1-7: TKI (Dasatinib 140mg orally once daily [100mg for patients >70 years]). Administer for 4 weeks, with:

Day 1: Vincristine 2mg IV (1mg for patients >70 years) with:

Days 1-2: Dexamethasone 40mg (20mg for patients >70 years).

Consolidation Therapy – Cycle A:

Day 1: TKI (Dasatinib 100mg orally once daily), followed by:

Day 1: Methotrexate 1000mg/m2 IV (500mg/m2 for patients >70 years)

Day 2: Asparaginase 10,000 IU/m2 IM (5,000 IU/m2 IM for patients >70 years).

Repeat every 4 weeks for 3 cycles alternating with Consolidation Therapy Cycle B.

Consolidation Therapy – Cycle B:

Days 1,3,5: Cytarabine 1000mg/m2 IV (500mg/m2 IV for patients >70 years) every 12 hours.

Repeat every 4 weeks for 3 cycles alternating with Consolidation Therapy Cycle A.

Maintenance Therapy – Cycle A:

Days 1-28: TKI (Dasatinib 100mg orally once daily).

Repeat cycle every 4 weeks alternating with Maintenance Therapy – Cycle B until 24 months from diagnosis.

Maintenance Therapy – Cycle B:

Days 1-28: 6-Mercaptopurine 60mg/m2

Days 1: Methotrexate 35mg/m2 orally weekly.

Repeat cycle every 4 weeks alternating with Maintenance Therapy – Cycle A until 24 months from diagnosis.

Maintenance Therapy – Cycle C:

Day 1: Vincristine 2mg IV (1mg for patients >70 years)

Days 1-2: Dexamethasone 40mg (20mg for patients >70 years).

Administer every 3 months during Maintenance Therapy until 24 months from diagnosis.

• EWALL + Nilotinib (EWALL-Ph-002)

Nilotinib administered at 400mg twice daily during induction and then continuously through consolidation and maintenance therapy.

High Intensity

Hyper CVAD with TKI alternating with High-Dose Methotrexate/ Cytarabine (with dose-reduced Cytarabine to 1000mg/m2)12,13,e

• Dasatinib-based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Days 1-14: Dasatinib 100mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine 1,000mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-14: Dastinib 100mg orally daily.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

• Ponatinib-Based Therapy

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mensa 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Days 1-14: Ponatinib 45mg orally daily (cycle 1), followed by:

Days 1-21: Ponatinib 30mg orally daily (cycles 2-4).

Repeat cycle every 3 weeks for 4 weeks alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine 1,000mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Days 1-21: Ponatinib 30mg orally.

Repeat cycle every 3 weeks for 4 cycles alternating with Cycle A.

Ph (-) Disease

Low Intensity

Vincristine + Prednisone34

Prednisone 60mg/m2 in divided doses for 2-4 weeks and then tapered off over about another 10-14 days

Vincristine 1-3.3mg/m2 IV (typically within range of 1.5-2.0mg/m2) weekly in 2-4 doses.

POMP10,35

Days 1-5: Prednisone 200mg orally

Days 1: Vincristine 2mg IV (maximum dose: 2mg)

Days 1-5: 6-Mercaptopurine 1,000/m2 IV over 1 hour

Days 1-5: Methotrexate 10mg/m2 IV over 1 hour.

Repeat cycle every 4 weeks.

Moderate Intensity

GMALL32

See Reference and NCCN Acute Lymphoblastic Leukemia Guidelines.

GRAALL24

Prephase Treatment:

Days (-7)-(-1): Prednisone 60mg/m2 orally

Between Days (-7) and (-4): Methotrexate 15mg intrathecal.

Induction Therapy:

Days 1-14: Prednisone 60mg/m2 orally

Days 1,8,15,22: Vincristine 2mg IV

Days 1-3: Daunorubicin 50mg/m2 IV

Days 15,16: Daunorubicin 30mg/m2 IV

Days 8,10,12: L-Asparaginase 6,000 IU/m2 daily IV over 1 hour (not done if CNS involvement), then,

Days 20,22,24,26,28: L-Asparaginase 6,000 IU/m2 daily IV over 1 hour

Day 1: Cyclophosphamide 750mg/m2 IV over 3 hours

Day 15: Cyclophosphamide 750mg/m2 IV over 3 hours (1 infusion) OR Days 15-17: Cyclophosphamide 300mg/m2 over 3 hours every 12 hours (6 infusions)f

Day 18 to neutrophil recovery: Lenograstim 263 mcg/day subcutaneous or IV.

Salvage Reintroduction Therapy:

Days 1-3: Idarubicin 12mg/m2 IV over 1 hour

Days 1-4 (8 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Day 9 to neurotrophil recovery: Lenograstim 263 mcg subcutaneous or IV daily.

Interphase-1 Therapy:

Day 1: Vincristine 2mg IV

Day 1: Dexamethasone 40mg orally daily.

Consolidation Therapy I – Block 1:

Days 1,2 (4 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Days 1,2: Dexamethasone 10mg orally every 12 hours

Day 3: L-Asparaginase (E coli): 10,000 IU/m2 IV over 1 hour

Days 9-13: Lenograstim 263 mcg orally or IV

Consolidation Therapy I – Block 2:

Day 15: Vincristine 2mg IV

Day 15: Methotrexate 3,000 mg/m2 continuous IV over 24 hours

Day 16: L-Asparaginase 10,000 IU/m2 IV over 1 hour

Day 15-21: 6-Methotrexate 60mg/m2 orally

Days 23-27: Lenograstim 263 mcg SC or IV daily

Consolidation Therapy I – Block 3:

Day 29: Methotrexate 25mg/m2 IV

Days 29,30: Cyclophosphamide 500mg/m2 IV daily over 3 hoursf

Days 28,30: Etoposide 75mg/m2 IV over 1 hour.

Day 31 to neutrophil recovery: Lenograstim 263 mcg SC or IV daily.

Consolidation Therapy II:

Block 4 – identical to Block 1

Block 5 – identical to Block 2

Block 6 – identical to Block 3

Late Intensification Therapy (if CR after 1st course):

Days 1-14: Prednisone 60mg/m2 orally

Day 1,8,15,22: Vincristine 2mg IV

Day 1-3,15,16: Daunorubicin 30mg/m2 IV

Day 8,10,12,20,22,24,26,28: L-Asparaginase 6,000 IU/m2 IV over 1 hour

Day 1: Cyclophosphamide 750mg/m2 IV over 3 hours, then,f

Day 15 (1 infusion): Cyclophosphamide 750mg/m2 over 3 hours OR Days 15-17 (6 infusions): 300mg/m2 over 3 hours every 12 hours

Day 18 to neutrophil recovery: Lenograstim 263mcg subcutaneous or IV daily.

Late Intensification Therapy (if late CR):

Days 1-3: Idarubicin 9mg/m2 IV over 1 hour daily

Day1-4 (8 infusions): Cytarabine 2,000mg/m2 IV over 2 hours every 12 hours

Day 9 to neutrophil recovery: Lenograstim 263 mcg SC or IV daily.

Consolidation Therapy III:

Repeat Consolidation Therapy I Blocks 1-3.

Maintenance Therapy

Day 1 (month 1-12): Vincristine 2mg IV

Day 1-7 (month 1-12): Prednisone 40mg/m2 orally daily

Months 1-24: 6-Mercaptopurine 60mg/m2 orally daily

Months 1-24: Methotrexate 25mg/m2 orally weekly.

Inotuzumab Ozogamicin + Mini-Hyper CVD (for B-ALL)36

Cycle A (Cycles 1,3,5,7):

Days 1-3: Cyclophosphamide 150mg/m2 every 12 hoursf

Days 1-4, 11-14: Dexamethasone 20mg

Days 1-8: Vincristine IV (2mg, flat dose)

Repeat cycle every 4 weeks for 4 cycles alternating with Cycle B.

Cycle B (Cycles 2,3,6,8):

Day 1: Methotrexate 250mg/m2

Days 2,3: Cytarabine 580mg/m2 every 12 hours

Repeat cycle every 4 weeks for 4 cycles alternating with Cycle A.

Note: Day 3 (Cycle 1): Inotuxumab Ozogamicin 1.3mg/m2

Day 3 (Cycles 2-4): Inotuzumab Ozogamicin 1.0mg/m2

Note: Rituximab administered during first 4 cycles for patients with CD-20 positive disease.

Modified DFCI 91-0137

Induction Therapy (4 weeks):

Days 1-4, 9-12: Dexamethasone 40mg orally

Days 1,2: Doxorubicin 30mg/m2 IV

Days 1,8,15: Vincristine 2mg IV

Day 3: Methotrexate 40mg/m2 IV

Day 1: Cytarabine 70mg intrathecal

Day 15: Cytarabine 40mg/Methotrexate 12mg/Hydrocortisone 15mg intrathecal

Day 4: Asparaginase 12,000 IU/m2 IM.

Central Nervous System Therapy (3 weeks):

Day 1: Vincristine 2mg IV

Day 1: Doxorubicin 30mg/m2 IV

Days 1-14: 6-Mercaptopurine 50mg/m2 orally

Days 1,4,8,11: Cytarabine 40mg/Methotrexate 12mg/Hydrocortisone 15mg intrathecal.

Intensification Therapy (21 weeks; 7 x 3 week cycles):

Days 1-5: Dexamethasone 6mg orally twice daily

Day 1: Vincristine 2mg IV

Day 1: Doxorubicin 30mg/m2 IV

Days 1-14: 6-Mercaptopurine 50mg/m2 orally

Every 18 weeks: Cytarabine 40mg/Methotrexate 12mg/Hydrocortisone 15mg intrathecal

Days 1,8,15: Asparaginase 6,000 IU/m2 IM

Maintenance Therapy (72 weeks: 24 x 3 week cycles):

Days 1-5: Dexamethasone 6mg orally twice daily

Day 1: Vincristine 2mg IV

Days 1-14: 6-Mercaptopurine 50mg/m2 orally

Days 1,8,15: Methotrexate 30mg/m2 orally

Every 18 weeks: Cytarabine 40mg/Methotrexate 12mg/Hydrocortisone 15mg intrathecal.

PETHEMA – Based Regimen: ALLOLD0738

Pre-Phase Regimen:

Days (-5)-(-1): Dexamethasone 10mg/m2 IV

Induction Therapy 1:

Days 1,8: Vincristine 1mg IV

Days 1,2,8,9: Idarubicin 10mg IV

Days 1,2,8-11: Dexamethasone 10mg/m2 IV.

Induction Therapy 2:

Days 15-17: Cyclophophamide 300mg/m2 IVe

Days 16-19, 23,26: Cytarabine 60mg/m2 IV.

Administer Induction Therapy 1 and 2 over a 4-week period.

Consolidation Therapy – Cycle A:

Day 1: Methotrexate 1,000mg/m2 IV continuous 24 hour infusion followed by folinic acid rescue

Day 2: Asparaginase (E. coli) 10,000 IU/m2 IV.

Consolidation Therapy – Cycle B:

Days 1,3,5: Cytarabine 1,000mg/m2 IV.

Note: Consolidation therapy consists of 6 alternating cycles of Cycle A (cycles 1,3, and 5) and Cycle B (cycles 2,4, and 6).

Maintenance Therapy:

6-Mercaptopurine 60mg/m2 orally daily

Methotrexate 25mg/m2 IM weekly.

Reinduction Cycles:

Days 1,2: Dexamethasone 40mg orally or IV

Day 1: Vincristine 1mg IV.

Administer every 3 months in the first year, and every 3 months in the second year.

Note: Administer maintenance therapy with reinduction pulses for a total treatment duration of 2 years.

High Intensity

CALGB 911139

Induction Therapy (4 weeks):

Day 1: Cyclophosphamide 800mg/m2 IVf

Days 1-3: Daunorubicin 30mg/m2 IV

Days 1-21: Prednisone 60mg/m2 orally or IV once daily

Days 5,8,11,15,18,22: L-Asparaginase (E. coli): 6,000 IU/m2 subcutaneous or IM.

Early Intensification (4 weeks; repeat once):

Day 1: Methotrexate 15mg intrathecal

Day 1: Cyclophosphamide 1000mg/m2 IVf

Days 1-14: 6-Mercaptopurine 60mg/m2 orally

Days 1-4,8-11: Cytarabine 75mg/m2 subcutaneous

Days 15,22: Vincristine 2mg IV

Days 15,18,22,25: L-Asparaginase (E. coli): 6,000 IU/m2 subcutaneous or IM.

CNS Prophylaxis and Interim Maintenance (12 weeks):

Days 1-12: Cranial irradiation

Days 1,8,15,22,29: Methotrexate 15 mg intrathecal

Days 1-70: 6-Mercaptopurine 60mg/m2 orally

Days 36,43,50,57,64: Methotrexate 20mg/m2 orally.

Late Intensification (8 weeks):

Days 1,8,15: Doxorubicin 30mg/m2 IV

Days 1,8,15: Vincristine 2mg IV

Days 1-14: Dexamethasone 10mg/m2 orally

Day 29: Cyclophosphamide 1,000mg/m2 IVf

Days 29-42: 6-Thioguanine 60mg/m2 orally

Days 29-32, 36-39: Cytarabine 75mg/m2 subcutaneous daily.

Prolonged Maintenance (every 4 weeks until 2 years from diagnosis):

Day 1: Vincristine 2mg IV

Days 1-5: Prednisone 60mg/m2 orally

Days 1-28: 6-Mercaptopurione 60mg/m2 orally

Days 1,8,15,22: Methotrexate 20mg/m2 orally.

Hyper CVAD high-dose Methotrexate/ Cytarabine (with Cytarabine dose reduced to 1,000mg/m2)10,11,40

Cycle A:

Days 1-3: Cyclophosphamide 300mg/m2 IV over 3 hours every 12 hours for 6 dosesf

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily starting 15 minutes before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide is started.

Day 4: Doxorubicin 50mg/m2 IV push OR IV continuous infusion over 24 hours

Days 4 and 11: Vincristine 2mg IV over 5-10 minutes

Days 1-4, 11-14: Dexamethasone 40mg IV OR orally daily

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Repeat every 3 weeks for 4 cycles alternating with Cycle B.

Cycle B:

Day 1: Methotrexate 200mg/m2 IV over 2 hours, then 800mg/m2 IV continuous infusion over 22 hours. (Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.)

Day 2: Leucovorin 50mg IV over 15 minutes administered 12 hours after completion of 22-hour Methotrexate infusion, then 15mg IV over 15 minutes OR orally every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.05 micromol/L)

Days 2-3: Cytarabine (age ≥60 years) 1,000 mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 2: Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal

Repeat every 3 weeks for 4 cycles alternating with Cycle A.

▶Relapsed/Refractory ALL1,a,p

PROTOCOL1,b

REGIMEN and DOSING

Ph (+) Diseasep-t

Other Recommended Regimens

Blinatumomab (for B-ALL; TKI intolerant/ refractory) (Category 1)41,42

Prephase Therapy: Before start of treatment until Cycle 1, induction, Day 1: Dexamethasone 10mg/m2 orally or IV daily (maximum 24mg/day), followed by:

Cycle 1 Induction Therapy:

Days 1-7: Blinatumomab 9mcg IV continuous infusion over 24 hours daily

Days 8-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily

Administer for one 6-week cycle (4 weeks on followed by 2 weeks off treatment), followed by:

Cycle 2 Induction Therapy:

Days 1-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily.

Administer for one 6-week cycle (4 weeks on followed by 2 weeks off treatment).

Consolidation Therapy:

Days 1-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily.

Repeat cycle every 6 weeks (4 weeks on followed by 2 weeks off treatment) for 3 cycles.

Continued Therapy:

Days 1-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily.

Repeat 12-week cycle (4 weeks on followed by 8 weeks off treatment) for 4 cycles.

Note: For patients <45kg, BSA-based dosing should be used. Blinatumomab may be given up to a total of 9 cycles (2 cycles of induction followed by 3 cycles of consolidation followed by 4 cycles of continued therapy.

Bosutinib43,q,r

Bosutinib 400mg twice daily or 600mg twice daily.

Dasatinib44,q

Dasatinib 140mg orally once daily or 70mg orally twice daily.

Imatinib45,q

Imatinib 400mg or 600mg once daily.

Inotuzumab Ozogamicin (for B-ALL; TKI intolerant/ refractory)46

Day 1: Inotuzumab Ozogamicin 0.8mg/m2 IV

Days 8,15: Inotuzumab Ozogamicin 0.5mg/m2 IV

Administer for one 21-day cycle, then repeat subsequent cycles every 4 weeks for up to 6 cycles.

Once CR or CRi achieved, dose of Inotuzumab Ozogamicin reduced to 0.5mg/m2 IV.

MOpAD + TKI with and without Rituximab (Category 2B)47

Days 1,15: Methotrexate 200mg/m2 IV (reduced by 50% for creatinine clearance)

Days 1,8,15: Vincristine 1.4mg/m2 IV (reduced dose to 1mg for pre-existing neuropathy and/or bilirubin 2-3mg/dL, hold for bilirubin >3mg/dL); maximum dose 2mg)

Days 2,16: Pegylated-L-Asparaginase 2,500 IU/m2 IV (no capping of dose; decrease by 50% if direct bilirubin between 2 and 3mg/dL; hold for bilirubin ≥3mg/dL, especially serous pancreatitis, thrombosis not controlled with anticoagulation, or disseminated intravascular coagulation)

Days 1-4, 15-18: Dexamethasone 40mg IV or orally

Dasatinib 70-100mg orally daily, Imatinib 400-800mg orally daily, or Nilotinb 200-400 mg orally once daily in combination with chemotherapy.

For patients with CD20-positive leukemia:

Days 1,15: Rituximab 375mg/m2 IV during the first 4 cycles.

Nilotinib48,q,r

Nilotinib 200-400mg orally once daily.

Ponatinib49,q,s,t

Ponatinib 45 mg orally once daily.

Tisagenlecleucel (for patients <26 years with refractory disease or ≥2 relapses and failure of 2 TKIs)50

See NCCN Acute Lymphoblastic Leukemia Guidelines1

Ph (-) Diseaseu,v

Preferred Regimens

B-ALL

Blinatumomab (Category 1)41,42

Prephase Therapy: Before start of treatment until Cycle 1, induction,
Day 1: Dexamethasone 10mg/m2 orally or IV daily (maximum 24mg/day), followed by:

Cycle 1 Induction Therapy:

Days 1-7: Blinatumomab 9mcg IV continuous infusion over 24 hours daily

Days 8-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily

Administer for one 6-week cycle (4 weeks on followed by 2 weeks off treatment), followed by:

Cycle 2 Induction Therapy:

Days 1-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily.

Administer for one 6-week cycle (4 weeks on followed by 2 weeks off treatment).

Consolidation Therapy:

Days 1-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily.

Repeat cycle every 6 weeks (4 weeks on followed by 2 weeks off treatment) for 3 cycles.

Continued Therapy:

Days 1-28: Blinatumomab 28mcg IV continuous infusion over 24 hours daily.

Repeat 12-week cycle (4 weeks on followed by 8 weeks off treatment) for 4 cycles.

Note: For patients <45kg, BSA-based dosing should be used.

Blinatumomab may be given up to a total of 9 cycles (2 cycles of induction followed by 3 cycles of consolidation followed by 4 cycles of continued therapy).

Inotuzumab Ozogamicin (Category 1)46

Day 1: Inotuzumab Ozogamicin 0.8mg/m2 IV

Days 8,15: Inotuzumab Ozogamicin 0.5mg/m2 IV

Administer for one 21-day cycle, then repeat subsequent cycles every 4 weeks for up to 6 cycles.

Once CR or CRi achieved, dose of Inotuzumab Ozogamicin reduced to 0.5mg/m2 IV.

Tisagenlecleucel (patients <26 years with refractory disease or ≥2 relapses)50

See NCCN Acute Lymphoblastic Leukemia Guidelines1

T-ALL

Other Recommended Regimens

Nelarabine (for T-ALL)51,52

Days 1,3,5: Nelarabine (age >16 years) 1,500mg/m2 IV over 2 hours.

Repeat cycle every 3 weeks.

OR

Day 1-5: Nelarabine (age ≤21 years) 650mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

Nelarabine, Etoposide, Cyclophosphamide (for T-ALL)53,54

Days 1-5: Etoposide 100mg/m2 IV

Days 1-5: Cyclophosphamide 440mg/m2 IVf

Days 7(8)-11(12): Nelarabine 650mg/m2 IV

Intrathecal Methotrexate or triplet intrathecal therapy (Methotrexate, Cytarabine, Hydrocortisone) typically preceding a nelarabine dose by 6 hours or following Nelarabine by 2 days.

B-ALL or T-ALL

Other Recommended Regimens

Alkylator Combination Regimen55

Days 1-5: Etoposide 100mg/m2 IV over 1.5 hours

Days 1-3: Mitoxantrone 8mg/m2 IV over 1 hour

Days 1-5: Ifosfamide 1/5mg/m2 IV over 30 minutes

All patients received Mesna 120mg/m2 IV immediately prior to first dose of Ifosfamide and thereafter received a continuous infusion of Mesna 1,000mg/m2 daily for 6 days.

Augmented Hyper CVAD56

Cycle A: (every 21-35 days)

Days 1-3: Cyclophosphamide 300mg/m2 IV every 12 hoursf, with:

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours daily

Day 4: Doxorubicin 50mg/m2 IV over 24 hours

Days 1,8,15: Vincristine 2mg IV

Days 1-4, 15-18: Dexamethasone 80mg IV or orally

Day 1: Pegaspargase 2,500 units/m2 IV.

Repeat every 21-35 days for 4 cycles alternating with Cycle B.

Cycle B (every 21-35 days):

Day 1: Methotrexate 1,000mg/m2 over 24 hours

Days 2,3: Cytarabine 3,000m/m2 IV every 12 hours once serum Methotrexate levels at the end of infusion reached ≤20 umole/L.

IV alkalinization used to promote excretion of Methotrexate in all course.

Calcium Leucovorin 50mg IV given 12 hours after completion of Methotrexate, then 15mg given every 6 hours for 8 doses or until Methotrexate levels were <0.1 umol/L. Oral Acetazolamide given for urine pH <7.0.

Cycle B (every 21-35 days): (continued)

Day 4: Doxorubicin 50mg/m2 IV over 24 hours

Days 1,8,15: Vincristine 2mg IV

Days 1-4, 15-18: Dexamethasone 80mg IV or orally

Day 5: Pegaspargase 2,500 units/m2 IV.

Repeat every 21-35 days for 4 cycles alternating with Cycle A.

Filgrastim 10mcg/kg subcutaneous daily started 24 hours after chemotherapy completion and continued until the postnadir ANC reached ≥1 x 109/L.

CNS Prophylaxis (first 2 courses; 4 treatments total):

Day 2: Alternating Methotrexate 12mg intrathecal

Day 7: Cytarabine 100mg intrathecal.

Maintenance Therapy (following Induction and Intensified Consolidation) (up to 12 months):

Mercaptopurine 50mg orally three times daily

Methotrexate 20mg/m2 orally weekly

Vincristine 2mg IV every 28-55 days

Days 1-5 starting with Vincristine: Prednisone 200mg orally daily.

Clofarabine57

Clofarabine 52mg/m2 IV over 2 hours daily for 5 consecutive days every 2-6 weeks for up to 12 cycles.

Clofarabine-containing regimens58

• Clofarabine/Cyclophosphamide/Etoposide Regimen

Induction Therapy:

Clofarabine 40mg/m2 IV over 2 hours daily, followed by:

Etoposide 100mg/m2 IV over 2 hours daily, with:

Cyclophosphamide 440mg/m2 IV over 1 hour.f

Administered for 5 consecutive days as 1 or 2 induction cycles.

Consolidation Therapy:

1-3 cycles (4 days of chemotherapy).

Maximum of 4 cycles (induction + consolidation).

A daily dose of Prednisone 0.5mg/kg was administered.

Cytarabine-containing regimens59

Days 1-5: Cytarabine 3,000mg/m2 IV over 3 hours

Day 3: Idarubicin 40mg/m2 IV rapid infusion

Starting on Day 7: Filgrastim (G-CSF) 5mcg/kg subcutaneous twice daily (every 12 hours) and continued until ANC >5,000/uL

Days 2,4: Methotrexate 6mg/m2 intrathecal.

FLAG-IDA60

Days 1-5: Fludarabine 30mg/m2 IV over 30 minutes

Days 1-5: Cytarabine 2,000mg/m2 IV over 4 hours

Days 1-3: Idarubicin 10mg/m2 IV

G-CSF 5mcg/kg subcutaneous commenced 24 hours after completion of chemotherapy and continued until neutrophils >1.5 x 109/L.

FLAM61

Days 1,2,8,9: Fludarabine 15mg/m2 over 30 minutes every 12 hours, followed by:

Days 1,2,8,9: Cytarabine 100mg/m2 IV over 45 minutes

Days 3,10: Mitoxantrone 10mg/m2 over 20 minutes.

Inotuzumab Ozogmaicin + Mini-HyperCVD (for B-ALL)36

Cycle A (Cycles 1,3,5,7):

Days 1-3: Cyclophosphamide 150mg/m2 every 12 hoursf

Days 1-4, 11-14: Dexamethasone 20mg

Days 1-8: Vincristine IV (2mg, flat dose)

Repeat cycle every 4 weeks for 4 cycles alternating with Cycle B.

Cycle B (Cycles 2,3,6,8):

Day 1: Methotrexate 250mg/m2

Days 2,3: Cytarabine 580mg/m2 every 12 hours

Repeat cycle every 4 weeks for 4 cycles alternating with Cycle A.

Note:

Day 3 (Cycle 1): Inotuxumab Ozogamicin 1.3mg/m2

Day 3 (Cycles 2-4): Inotuzumab Ozogamicin 1.0mg/m2

Note: Rituximab administered during first 4 cycles for patients with CD-20 positive disease.

MOpAD Regimen47

Days 1,15: Methotrexate 200mg/m2 IV (reduced by 50% for creatinine clearance)

Days 1,8,15: Vincristine 1.4mg/m2 IV (reduced dose to 1mg for pre-existing neuropathy and/or bilirubin 2-3mg/dL, hold for bilirubin >3mg/dL maximum dose 2mg)

Days 2,16: Pegylated-L-Asparaginase 2,500 IU/m2 IV (no capping of dose; decrease by 50% if direct bilirubin between 2 and 3mg/dL; hold for bilirubin ≥3mg/dL, especially serous pancreatitis, thrombosis not controlled with anticoagulation, or disseminated intravascular coagulation)

Days 1-4, 15-18: Dexamethasone 40mg IV or orally

For patients with CD20-positive ALL:

Days 1,15: Rituximab 375mg/m2 IV during the first 4 cycles.

Vincristine Sulfate Liposome Injection62

Days 1,8,15,22: Vincristine Sulfate Liposome Injection 2.25mg/m2 IV over 60 minutes.

Repeat cycle every 4 weeks.

 a.  While these guidelines pertain primarily to patients with leukemia, patients with lymphoblastic lymphoma (LL) (B- or T-cell) also benefit from ALL-like regimens versus traditional lymphoma therapy. Such patients should be treated in a center that has experience with LL.

 b.  All regimens include CNS prophylaxis with systemic therapy (eg, methotrexate, cytarabine) and/or Intrathecal (IT) therapy (eg, IT methotrexate, IT cytarabine, triple IT therapy with methotrexate, cytarabine, corticosteroid).

 c. The ALL Panel considers AYA to be within the age range of 15-39 years. However, this age is not a firm reference point because some of the recommended regimens have not been comprehensively tested across all ages.

 d.  Add tyrosine kinase inhibitors (TKIs) to maintenance regimen; optimal duration is unknown. Monthly vincristine/prednisone pulses (for 2-3 years). May include weekly methotrexate + daily 6-Mercaptopurine as tolerated. For patients receiving 6-Mercaptopurine, consider testing for TPMT gene polymorphisms, particularly in patients who develop severe neutropenia after starting 6-Mercaptopurine. Dose modifications for antimetabolites in maintenance should be consistent with the chosen treatment regimen. It may be necessary to reduce dose/ eliminate antimetabolite in the setting of myelosuppression and/or hepatotoxicity.

 e. TKI options include (in alphabetical order): Bosutinib, Dasatinib, Imatinib, Nilotinib, or Ponatinib. Dasatinib and Imatinib are the preferred TKIs for induction therapy; Ponatinib is also preferred for the hyper-CVAD regimen. Not all TKIs have been directly studied within the context of each specific regimen and the panel notes that there are limited data for Bosutinib in Ph+ ALL. Use of a specific TKI should account for the anticipated/prior TKI intolerance and disease-related features.

  f. Oral hydration is strongly encouraged with cyclophosphamide; poorly hydrated patients may need supplemental IV hydration. Patients should attain combined oral and IV hydration of 2000-3000 mL/day on day of chemotherapy.

 g. CNS1=patients with white blood cell (WBC) count in CSF <5 and having no blasts in the CSF, CNS2=patients with WBC count in CSF <5 and having blasts in the CSF, CNS3=patients with WBC count in CSF ≥5 and having blasts in the CSF.

 h. Maintenance regimen: Weekly methotrexate + daily 6-Mercaptopurine + monthly vincristine/prednisone pulses (duration based on regimen). For patients receiving 6-Mercaptopurine, consider testing for TMPT gene polymorphisms, particularly in patients who develop severe neutropenia after starting 6-MP. Dose modifications for antimetabolites in maintenance should be consistent with the chosen treatment regimen. It may be necessary to reduce dose/eliminate antimetabolite in the setting of myelosuppression and/or hepatotoxicity.

  i. Pegasparagase may be substituted with calaspargase pegol-mknl, an asparagine-specific enzyme, in patients ≤21 years for more sustained asparaginase activity. Silverman LB, et al. Blood. 2016;128:175; Angiolillo AL, et al. J Clin Oncol. 2014;32:3874-3882.63,64

  j. Older adults (defined as those aged 65 years and older) benefit from therapy, in spite of higher treatment-related morbidity and mortality.

 k. Careful assessment of comorbid conditions, performance status, and ability to attend to activities of daily living (ADLs) and instrumental ADLs (IADLs) is important when deciding treatment intensity.

  l. Dose reduction of pegylated asparaginase (1000 IU/m2), anthracycline (50% dose), and/or other myelosuppressive agents may be warranted.

m.  The categorization of regimens as low, moderate, or high intensity is based on 2 factors: 1) the presence of absence of myelosuppressive cytotoxic agents, and 2) the relative dose intensity of the included agents.

 n. All regimens should include CNS prophylaxis, antimicrobial prophylaxis, and growth factor support.

 o. For appropriate fit individuals achieving remission, consideration of autologous or reduced-intensity allogeneic SCT may be appropriate.

 p. The safety of relapsed/refractory regimens in older adults (≥65 years) has not been established.

 q. Bosutinib is contraindicated in patients with disease characterized by BCR-ABL1 mutations T315I, V299L, G250E, F317L; Dasatinib is contraindicated in patients with disease characterized by BCR-ABL1 mutations T315L/A, F317L/V/I/C, V299L; Nilotinib is contraindicated in patients with disease characterized by BCR-ABL1 mutations IT315I, Y253H, E255K/V; F359V/C/I, G250E.

  r. Bosutinib has minimal activity against F317L mutation. Nilotinib may be preferred over bosutinib in patients with F317L mutation.

 s. Ponatinib is a treatment option for patients with a T315I mutation and/or for patients for whom no other TKI is indicated.

  t. Ponatinib has activity against T315I mutations and is effective in treating patients with resistant or progressive disease on multiple TKIs. However, it is associated with a high frequency of serious vascular events (eg, strokes, heart attacks, tissue ischemia). The FDA indications are for the treatment of adult patients with T315I-positive, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and for the treatment of patients with Ph+ ALL for whom no other TKI therapy is indicated.

  u. The regimens for relapsed/refractory, Philadelphia-negative ALL may be considered for Philadephia-positive ALL refractory to TKIs.

 v. For patients in late relapse (>3 years from initial diagnosis), consider treatment with the same induction regimen.

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(Revised 4/2020; NCCN Acute Lymphoblastic Leukemia Guidelines v1.2020) © 2020 by Haymarket Media, Inc.